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1. Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration

Author: Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert W.), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan L.), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Van der Heijden, J.F. (Jeroen F.), Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), van Tintelen, J.P. (J Peter), Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, James, C.A. (Cynthia A.), Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert W.), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan L.), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Van der Heijden, J.F. (Jeroen F.), Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), van Tintelen, J.P. (J Peter), Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, and James, C.A. (Cynthia A.)
Abstract: BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. METHODS: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. RESULTS: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism. CONCLUSION
Published: 2021
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2. Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy

Author: Schuldt, M. (Maike), Pei, J. (Jiayi), Harakalova, M. (Magdalena), Dorsch, L.M. (Larissa M.), Schlossarek, S. (Saskia), Mokry, M. (Michal), Knol, J.C. (Jaco), Pham, T.V. (Thang V.), Schelfhorst, T. (Tim), Piersma, S.R. (Sander R.), Dos Remedios, C. (Cris), Dalinghaus, M. (Michiel), Michels, M. (Michelle), Asselbergs, F.W. (Folkert W.), Moutin, M.-J. (Marie-Jo), Carrier, L. (Lucie), Jimenez, C.R. (Connie), Velden, J. (Jolanda) van der, Kuster, D.W.D. (Diederik), Schuldt, M. (Maike), Pei, J. (Jiayi), Harakalova, M. (Magdalena), Dorsch, L.M. (Larissa M.), Schlossarek, S. (Saskia), Mokry, M. (Michal), Knol, J.C. (Jaco), Pham, T.V. (Thang V.), Schelfhorst, T. (Tim), Piersma, S.R. (Sander R.), Dos Remedios, C. (Cris), Dalinghaus, M. (Michiel), Michels, M. (Michelle), Asselbergs, F.W. (Folkert W.), Moutin, M.-J. (Marie-Jo), Carrier, L. (Lucie), Jimenez, C.R. (Connie), Velden, J. (Jolanda) van der, and Kuster, D.W.D. (Diederik)
Abstract: BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCMSMP), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCMSMN). Genotype-specific differences have been reported in cardiac function. Moreover, HCMSMN patients have later disease onset and a better prognosis than HCMSMP patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group. METHODS: A proteomics screen was performed in cardiac tissue from 39 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG mouse model was used to confirm functional relevance of our proteomic findings. RESULTS: In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of to
Published: 2021
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3. Temporal Evolution of Serum Concentrations of High-Sensitivity Cardiac Troponin During 1 Year After Acute Coronary Syndrome Admission

Author: van den Berg, V.J. (Victor J.), Oemrawsingh, R.M. (Rohit), Umans, V.A.W.M. (Victor), Kardys, I. (Isabella), Asselbergs, F.W. (Folkert W.), van der Harst, P. (Pim), Hoefer, I.E. (Imo), Kietselaer, B.L. (Bas), Lenderink, T. (Timo), Oude Ophuis, A.J.M. (Anthonius), van Schaik, R.H. (Ron H.), Winter, R.J. (Robbert) de, Akkerhuis, K.M. (Martijn), Boersma, H. (Eric), van den Berg, V.J. (Victor J.), Oemrawsingh, R.M. (Rohit), Umans, V.A.W.M. (Victor), Kardys, I. (Isabella), Asselbergs, F.W. (Folkert W.), van der Harst, P. (Pim), Hoefer, I.E. (Imo), Kietselaer, B.L. (Bas), Lenderink, T. (Timo), Oude Ophuis, A.J.M. (Anthonius), van Schaik, R.H. (Ron H.), Winter, R.J. (Robbert) de, Akkerhuis, K.M. (Martijn), and Boersma, H. (Eric)
Abstract: Background Detailed insights in temporal evolution of high-sensitivity cardiac troponin following acute coronary syndrome (ACS) are currently missing. We aimed to describe and compare the post-ACS kinetics of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT), and to determine their intra- and interindividual variation in clinically stable patients. Methods and Results We determined hs-cTnI (Abbott) and hs-cTnT (Roche) in 1507 repeated blood samples, derived from 191 patients with ACS (median, 8/patient) who remained free from adverse cardiac events during 1-year follow-up. Post-ACS kinetics were studied by linear mixed-effect models. Using the samples collected in the 6- to 12-month post-ACS time frame, patients were then considered to have chronic coronary syndrome. We determined (differences between) the average hs-cTnI and average hs-cTnT concentration, and the intra- and interindividual variation for both biomarkers. Compared with hs-cTnT, hs-cTnI peaked higher (median 3506 ng/L versus 494 ng/L; P<0.001) and was quicker below the biomarker-specific upper reference limit (16 versus 19 days; P<0.001). In the post-6-month samples, hs-cTnI and hs-cTnT showed modest correlation (rspearman=
Published: 2021
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4. A registry-based algorithm to predict ejection fraction in patients with heart failure

Author: Uijl, A., Lund, L.H., Vaartjes, I. (Ilonca), Brugts, J.J., Linssen, G.C.M., Asselbergs, F.W. (Folkert), Hoes, A.W. (Arno), Dahlström, U., Koudstaal, S., Savarese, G., Uijl, A., Lund, L.H., Vaartjes, I. (Ilonca), Brugts, J.J., Linssen, G.C.M., Asselbergs, F.W. (Folkert), Hoes, A.W. (Arno), Dahlström, U., Koudstaal, S., and Savarese, G.
Abstract: Aims Left ventricular ejection fraction (EF) is required to categorize heart failure (HF) [i.e. HF with preserved (HFpEF), mid-range (HFmrEF), and reduced (HFrEF) EF] but is often not captured in population-based cohorts or non-HF registries. The aim was to create an algorithm that identifies EF subphenotypes for research purposes. Methods and results We included 42 061 HF patients from the Swedish Heart Failure Registry. As primary analysis, we performed two logistic regression models including 22 variables to predict (i) EF≥ vs. <50% and (ii) EF≥ vs. <40%. In the secondary analysis, we performed a multivariable multinomial analysis with 22 variables to create a model for all three separate EF subphenotypes: HFrEF vs. HFmrEF vs. HFpEF. The models were validated in the database from the CHECK-HF study, a cross-sectional survey of 10 627 patients from the Netherlands. The C-statistic (discrimination) was 0.78 [95% confidence interval (CI) 0.77–0.78] for EF ≥50% and 0.76 (95% CI 0.75–0.76) for EF ≥40%. Similar results were achieved for HFrEF and HFpEF in the multinomial model, but the C-statistic for HFmrEF was lower: 0.63 (95% CI 0.63–0.64). The external validation showed similar discriminative ability to the development cohort. Conclusions Routine clinical characteristics could potentially be used to identify different EF subphenotypes in databases where EF is not readily available. Accuracy was good for the prediction of HFpEF and HFrEF but lower for HFmrEF. The proposed algorithm enables more effective research on HF in the big data setting.
Published: 2020
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5. Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF)

Author: Angermann, C.E. (Christiane), Assmus, B. (Birgit), Anker, S.D. (Stefan D.), Asselbergs, F.W. (Folkert W.), Brachmann, J. (Johannes), Brett, M.-E. (Marie-Elena), Brugts, J.J. (Jasper J.), Ertl, G. (Georg), Ginn, G. (Greg), Hilker, L. (Lutz), Koehler, F. (Friedrich), Rosenkranz, S. (Stephan), Zhou, Q. (Qian), Adamson, P.B. (Philip B.), Böhm, B., Angermann, C.E. (Christiane), Assmus, B. (Birgit), Anker, S.D. (Stefan D.), Asselbergs, F.W. (Folkert W.), Brachmann, J. (Johannes), Brett, M.-E. (Marie-Elena), Brugts, J.J. (Jasper J.), Ertl, G. (Georg), Ginn, G. (Greg), Hilker, L. (Lutz), Koehler, F. (Friedrich), Rosenkranz, S. (Stephan), Zhou, Q. (Qian), Adamson, P.B. (Philip B.), and Böhm, B.
Abstract: Aims: Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)-guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland. Methods and results: A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP-guided HF management. One-year rates of freedom from device- or system-related complications and from sensor failure (co-primary outcomes) were 98.3% [95% confidence interval (CI) 95.8–100.0] and 99.6% (95% CI 97.6–100.0), respectively. Survival rate was 86.2%. For the 12 months post- vs. pre-implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient-year; hazard ratio 0.38, 95% CI 0.31–0.48; P < 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P < 0.0001), and the 9-item Patient Health Questionnaire sum score improve
Published: 2020
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6. Strength of patient cohorts and biobanks for cardiomyopathy research

Author: Boer, R.A. (Rudolf) de, Nijenkamp, L.L.A.M. (Louise), Silljé, H.H.W. (H. H.W.), Eijgenraam, T.R. (T. R.), Parbhudayal, R., van Driel, B. (B.), Huurman, R. (Roy), Michels, M. (Michelle), Pei, J.Y. (Jia Yi), Harakalova, M. (Magdalena), van Lint, F.H.M. (F. H.M.), Jansen, M. (M.), Baas, A.F. (A. F.), Asselbergs, F.W. (Folkert), van Tintelen, J.P. (J. P.), Brundel, B.J.J.M. (Bianca), Dorsch, L.M. (L. M.), Schuldt, M. (M.), Kuster, D.W.D. (Diederik), Velden, J. (Jolanda) van der, Boer, R.A. (Rudolf) de, Nijenkamp, L.L.A.M. (Louise), Silljé, H.H.W. (H. H.W.), Eijgenraam, T.R. (T. R.), Parbhudayal, R., van Driel, B. (B.), Huurman, R. (Roy), Michels, M. (Michelle), Pei, J.Y. (Jia Yi), Harakalova, M. (Magdalena), van Lint, F.H.M. (F. H.M.), Jansen, M. (M.), Baas, A.F. (A. F.), Asselbergs, F.W. (Folkert), van Tintelen, J.P. (J. P.), Brundel, B.J.J.M. (Bianca), Dorsch, L.M. (L. M.), Schuldt, M. (M.), Kuster, D.W.D. (Diederik), and Velden, J. (Jolanda) van der
Abstract: In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.
Published: 2020
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7. H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts

Author: Pei, J. (Jiayi), Harakalova, M. (Magdalena), Treibel, T.A. (Thomas A.), Lumbers, R.T. (R Thomas), Boukens, B.J. (Bastiaan J.), Efimov, I.R. (Igor R.), van Dinter, J.T. (Jip T.), González, A. (Arantxa), López, B. (Begoña), El Azzouzi, H. (Hamid), van den Dungen, N. (Noortje), Van Dijk, C.G.M. (Christian G.M.), Krebber, M.M. (Merle M.), Ruijter, H.M. (Hester ) den, Pasterkamp, G. (Gerard), Duncker, D.J.G.M. (Dirk), Nieuwenhuis, E.E.S. (Edward), Weger, R.A. (Roel) de, Huibers, M.M. (Manon M.), Vink, A. (Ard), Moore, J.H. (Jason), Moon, J.C. (James C.), Verhaar, M.C. (Marianne), Kararigas, G. (Georgios), Mokry, M. (Michal), Asselbergs, F.W. (Folkert), Cheng, C. (Caroline), Pei, J. (Jiayi), Harakalova, M. (Magdalena), Treibel, T.A. (Thomas A.), Lumbers, R.T. (R Thomas), Boukens, B.J. (Bastiaan J.), Efimov, I.R. (Igor R.), van Dinter, J.T. (Jip T.), González, A. (Arantxa), López, B. (Begoña), El Azzouzi, H. (Hamid), van den Dungen, N. (Noortje), Van Dijk, C.G.M. (Christian G.M.), Krebber, M.M. (Merle M.), Ruijter, H.M. (Hester ) den, Pasterkamp, G. (Gerard), Duncker, D.J.G.M. (Dirk), Nieuwenhuis, E.E.S. (Edward), Weger, R.A. (Roel) de, Huibers, M.M. (Manon M.), Vink, A. (Ard), Moore, J.H. (Jason), Moon, J.C. (James C.), Verhaar, M.C. (Marianne), Kararigas, G. (Georgios), Mokry, M. (Michal), Asselbergs, F.W. (Folkert), and Cheng, C. (Caroline)
Abstract: BACKGROUND: H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes. RESULTS: We detected chromatin regions with differential acetylation activity (DARs; Padj. < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls. CONCLUSIONS: Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles
Published: 2020
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8. Prognostic biomarker soluble ST2 exhibits diurnal variation in chronic heart failure patients

Author: Crnko, S. (Sandra), Printezi, M.I. (Markella I.), Jansen, T.P.J. (Tijn P.J.), Leiteris, L. (Laurynas), van der Meer, M.G. (Manon G.), Schutte, H. (Hilde), van Faassen, M. (Martijn), du Pré, B.C. (Bastiaan C.), Jonge, N. (Nicolaas) de, Asselbergs, F.W. (Folkert W.), Gaillard, C.A. (Carlo), Kemperman, H. (Hans), Doevendans, P.A. (Pieter), Sluijter, J.P.G., Van Laake, L.W. (Linda W.), Crnko, S. (Sandra), Printezi, M.I. (Markella I.), Jansen, T.P.J. (Tijn P.J.), Leiteris, L. (Laurynas), van der Meer, M.G. (Manon G.), Schutte, H. (Hilde), van Faassen, M. (Martijn), du Pré, B.C. (Bastiaan C.), Jonge, N. (Nicolaas) de, Asselbergs, F.W. (Folkert W.), Gaillard, C.A. (Carlo), Kemperman, H. (Hans), Doevendans, P.A. (Pieter), Sluijter, J.P.G., and Van Laake, L.W. (Linda W.)
Abstract: Aim: Soluble suppression of tumorigenicity-2 (sST2) is a strong prognostic biomarker in heart failure. The emerging understanding of circadian biology in cardiovascular disease may lead to novel applications in prognosis and diagnosis and may provide insight into mechanistic aspects of the disease–biomarker interaction. So far, it is unknown whether sST2 exhibits a diurnal rhythm. Repeated measurements of sST2 may aid in clinical decision making. The goal of this study was to investigate whether sST2 exhibits diurnal variation in patients with heart failure with reduced ejection fraction (HFrEF) and in control subjects, thereby enhancing its diagnostic and prognostic values. Methods and results: The study comprised 32 subjects: 16 HFrEF patients and 16 controls. Blood was collected at seven subsequent time points during a 24 h time period. sST2, N-terminal pro-B-type natriuretic peptide (NT-proBNP), melatonin, and cortisol were measured from serum. Peak values of sST2 clustered at daytime (modal value: 5 p.m.) in 87.6% of all subjects (81.3% of patients, P = 0.021; 93.8% of controls, P = 0.001), and minimum concentrations at night-time (modal value: 5 a.m.) in 84.4% (87.5% of patients, P = 0.004 81.3% of controls, P = 0.021). A cosinor analysis of mean normalized sST2 values revealed significant cosine shaped 24 h oscillations of patients (P = 0.026) and controls (P = 0.037). NT-proBNP in contrast did not show a diurnal rhythm, while melatonin and cortisol patterns were intact in all subjects. Conclusions: sST2 exhibits a diurnal rhythm with lower values in the morning than in the late afternoon. This new insight could lead to refinement of its diagnostic and prognostic values through specified and consistent sampling times with repeated measurements. For example, by measuring sST2 during the afternoon, when levels are at their highest, false negatives on prognosis prediction could be avoided.
Published: 2020
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9. A mutation update for the FLNC gene in myopathies and cardiomyopathies

Author: Verdonschot, J.A.J. (Job A. J.), Vanhoutte, E.K. (Els), Claes, G. (Godelieve), Helderman-van den Enden, A.T.J.M. (Apollonia), Hoeijmakers, J.G.J. (Janneke), Hellebrekers, D.M.E.I. (Debby), de Haan, A. (Amber), Christiaans, I. (Imke), Lekanne Deprez, R.H., Boen, H.M. (Hanne M.), Van Craenenbroeck, E.M. (Emeline M.), Loeys, B.L. (Bart), Hoedemaekers, Y.M. (Yvonne), Marcelis, C. (Carlo), Kempers, M.J.E. (Marlies), Brusse, E. (Esther), Waning, J. (Jaap) van, Baas, A.F. (Annette F.), Dooijes, D. (Dennis), Asselbergs, F.W. (Folkert W.), Barge-Schaapveld, D.Q.C.M. (Daniela), Koopman, P. (Pieter), Wijngaard, A. (Arthur) van den, Heymans, S. (Stephane), Krapels, I.P.C. (Ingrid), Brunner, H.G., Verdonschot, J.A.J. (Job A. J.), Vanhoutte, E.K. (Els), Claes, G. (Godelieve), Helderman-van den Enden, A.T.J.M. (Apollonia), Hoeijmakers, J.G.J. (Janneke), Hellebrekers, D.M.E.I. (Debby), de Haan, A. (Amber), Christiaans, I. (Imke), Lekanne Deprez, R.H., Boen, H.M. (Hanne M.), Van Craenenbroeck, E.M. (Emeline M.), Loeys, B.L. (Bart), Hoedemaekers, Y.M. (Yvonne), Marcelis, C. (Carlo), Kempers, M.J.E. (Marlies), Brusse, E. (Esther), Waning, J. (Jaap) van, Baas, A.F. (Annette F.), Dooijes, D. (Dennis), Asselbergs, F.W. (Folkert W.), Barge-Schaapveld, D.Q.C.M. (Daniela), Koopman, P. (Pieter), Wijngaard, A. (Arthur) van den, Heymans, S. (Stephane), Krapels, I.P.C. (Ingrid), and Brunner, H.G.
Abstract: Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrime
Published: 2020
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10. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author: Shah, S. (Sonia), Henry, A. (Albert), Roselli, C. (Carolina), Lin, H. (Honghuang), Sveinbjörnsson, G. (Garðar), Fatemifar, G. (Ghazaleh), Hedman, A.K. (Asa), Wilk, J.B. (Jemma), Morley, M.P. (Michael P.), Chaffin, M.D. (Mark D.), Helgadottir, H.T. (Hafdis), Verweij, N. (Niek), Dehghan, A. (Abbas), Almgren, P. (Peter), Andersson, C. (Charlotte), Aragam, K.G. (Krishna G.), Ärnlöv, J. (Johan), Backman, J.D. (Joshua D.), Biggs, M.L. (Mary L.), Bloom, H.L. (Heather L.), Brandimarto, J. (Jeffrey), Brown, M.R. (Michael R.), Buckbinder, L. (Leonard), Carey, D.J. (David J.), Chasman, D.I. (Daniel I.), Chen, X. (Xing), Chen, X. (Xu), Chung, J. (Jonathan), Chutkow, W. (William), Cook, J.P. (James P.), Delgado, G., Denaxas, S. (Spiros), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Dudley, S.C. (Samuel C.), Dunn, M.E. (Michael E.), Engström, G., Esko, T. (Tõnu), Felix, S.B. (Stephan B.), Finan, C. (Chris), Ford, I. (Ian), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Giedraitis, V. (Vilmantas), Giulianini, F. (Franco), Gottdiener, J.S. (John), Gross, S. (Stefan), Guðbjartsson, D.F. (Daníel F.), Gutmann, R. (Rebecca), Haggerty, C.M. (Christopher M.), Harst, P. (Pim) van der, Hyde, C.L. (Craig L.), Ingelsson, E. (Erik), Jukema, J.W. (Jan Wouter), Kavousi, M. (Maryam), Khaw, K.-T. (Kay-Tee), Kleber, M.E. (Marcus), Køber, L. (Lars), Koekemoer, A. (Andrea), Langenberg, C. (Claudia), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), London, B. (Barry), Lotta, L.A. (Luca A.), Lovering, R.C. (Ruth C.), Luan, J., Magnusson, P.K. (Patrik), Mahajan, A. (Anubha), Margulies, K.B. (Kenneth B.), Ye, S. (Shu), Melander, O. (Olle), Mordi, I.R. (Ify R.), Morgan, T. (Thomas), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Morrison, A.C. (Alanna C.), Nagle, M.W. (Michael W.), Nelson, C.P. (Christopher P.), Niessner, A. (Alexander), Niiranen, T. (Teemu), O’Donoghue, M.L. (Michelle L.), Owens, A.T. (Anjali T.), Palmer, C.N.A. (Colin N. A.), Parry, H.M. (Helen M.), Perola, M. (Markus), Portilla-Fernandez, E. (Eliana), Psaty, B.M. (Bruce M.), Abecasis, G. (Goncalo), Backman, J. (Joshua), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Banerjee, N. (Nilanjana), Baras, A. (Aris), Barnard, L. (Leland), Beechert, C. (Christina), Blumenfeld, A. (Andrew), Cantor, M. (Michael), Chai, Y. (Yating), Coppola, G. (Giovanni), Damask, A. (Amy), Dewey, F. (Frederick), Economides, A. (Aris), Eom, G. (Gisu), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Gurski, L. (Lauren), Guzzardo, P.M. (Paloma M.), Habegger, L. (Lukas), Hahn, Y. (Young), Hawes, A. (Alicia), van Hout, C. (Cristopher), Jones, M.B. (Marcus B.), Khalid, S. (Shareef), Lattari, M. (Michael), Li, A. (Alexander), Lin, N. (Nan), Liu, D. (Daren), Lopez, A. (Alexander), Manoochehri, K. (Kia), Marchini, J. (Jonathan), Marcketta, A. (Anthony), Maxwell, E.K. (Evan K.), McCarthy, S. (Shane), Mitnaul, L.J. (Lyndon), O’Dushlaine, C. (Colm), Overton, J.D. (John D.), Padilla, M.S. (Maria Sotiropoulos), Paulding, C. (Charles), Penn, J. (John), Pradhan, M. (Manasi), Reid, J.G. (Jeffrey G.), Schleicher, T.D. (Thomas D.), Schurmann, C. (Claudia), Shuldiner, A. (Alan), Staples, J.C. (Jeffrey C.), Sun, D. (Dylan), Toledo, K. (Karina), Ulloa, R.H. (Ricardo H.), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Yadav, A. (Ashish), Ye, B. (Bin), Rice, K.M. (Kenneth), Ridker, P.M. (Paul M.), Romaine, S.P.R. (Simon P. R.), Rotter, J.I. (Jerome I.), Salo, P. (Perttu), Salomaa, V. (Veikko), Setten, J. (Jessica) van, Shalaby, A.A. (Alaa A.), Smelser, D.T. (Diane T.), Smith, N.L. (Nicholas L.), Stender, S. (Steen), Stott, D.J. (David. J.), Svensson, P. (Per), Tammesoo, M.L., Taylor, K.D. (Kent D.), Teder-Laving, M. (Maris), Teumer, A. (Alexander), Thorgeirsson, G. (Guðmundur), Thorsteinsdottir, U. (Unnur), Torp-Pedersen, C. (Christian Tobias), Trompet, S. (Stella), Tyl, B. (Benoit), Uitterlinden, A.G. (Andre G.), Veluchamy, A. (Abirami), Völker, U. (Uwe), Voors, A.A. (Adriaan A.), Wang, X. (Xiaosong), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Weeke, P.E. (Peter E.), Weiss, R. (Ram), Wiggins, K.L. (Kerri L.), Xing, H. (Heming), Yerges-Armstrong, L.M. (Laura), Yu, B. (Bing), Zannad, F. (Faiez), Zhao, J.H. (Jing Hua), Hemingway, H., Samani, N.J. (Nilesh J.), McMurray, J.J.V. (John J. V.), Yang, J. (Jian), Visscher, P.M. (Peter M.), Newton-Cheh, C. (Christopher), Mälarstig, A. (Anders), Holm, H. (Hilma), Lubitz, S.A. (Steven), Sattar, N. (Naveed), Holmes, M.V. (Michael), Cappola, T.P. (Thomas P.), Asselbergs, F.W. (Folkert), Hingorani, A. (Aroon), Kuchenbaecker, K.B. (Karoline), Ellinor, P.T. (Patrick), Lang, C.C. (Chim C.), Stefansson, K. (Kari), Smith, J.G. (J Gustav), Vasan, R.S. (Ramachandran Srini), Swerdlow, D.I. (Daniel), Lumbers, R.T. (R. Thomas), Shah, S. (Sonia), Henry, A. (Albert), Roselli, C. (Carolina), Lin, H. (Honghuang), Sveinbjörnsson, G. (Garðar), Fatemifar, G. (Ghazaleh), Hedman, A.K. (Asa), Wilk, J.B. (Jemma), Morley, M.P. (Michael P.), Chaffin, M.D. (Mark D.), Helgadottir, H.T. (Hafdis), Verweij, N. (Niek), Dehghan, A. (Abbas), Almgren, P. (Peter), Andersson, C. (Charlotte), Aragam, K.G. (Krishna G.), Ärnlöv, J. (Johan), Backman, J.D. (Joshua D.), Biggs, M.L. (Mary L.), Bloom, H.L. (Heather L.), Brandimarto, J. (Jeffrey), Brown, M.R. (Michael R.), Buckbinder, L. (Leonard), Carey, D.J. (David J.), Chasman, D.I. (Daniel I.), Chen, X. (Xing), Chen, X. (Xu), Chung, J. (Jonathan), Chutkow, W. (William), Cook, J.P. (James P.), Delgado, G., Denaxas, S. (Spiros), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Dudley, S.C. (Samuel C.), Dunn, M.E. (Michael E.), Engström, G., Esko, T. (Tõnu), Felix, S.B. (Stephan B.), Finan, C. (Chris), Ford, I. (Ian), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Giedraitis, V. (Vilmantas), Giulianini, F. (Franco), Gottdiener, J.S. (John), Gross, S. (Stefan), Guðbjartsson, D.F. (Daníel F.), Gutmann, R. (Rebecca), Haggerty, C.M. (Christopher M.), Harst, P. (Pim) van der, Hyde, C.L. (Craig L.), Ingelsson, E. (Erik), Jukema, J.W. (Jan Wouter), Kavousi, M. (Maryam), Khaw, K.-T. (Kay-Tee), Kleber, M.E. (Marcus), Køber, L. (Lars), Koekemoer, A. (Andrea), Langenberg, C. (Claudia), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), London, B. (Barry), Lotta, L.A. (Luca A.), Lovering, R.C. (Ruth C.), Luan, J., Magnusson, P.K. (Patrik), Mahajan, A. (Anubha), Margulies, K.B. (Kenneth B.), Ye, S. (Shu), Melander, O. (Olle), Mordi, I.R. (Ify R.), Morgan, T. (Thomas), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Morrison, A.C. (Alanna C.), Nagle, M.W. (Michael W.), Nelson, C.P. (Christopher P.), Niessner, A. (Alexander), Niiranen, T. (Teemu), O’Donoghue, M.L. (Michelle L.), Owens, A.T. (Anjali T.), Palmer, C.N.A. (Colin N. A.), Parry, H.M. (Helen M.), Perola, M. (Markus), Portilla-Fernandez, E. (Eliana), Psaty, B.M. (Bruce M.), Abecasis, G. (Goncalo), Backman, J. (Joshua), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Banerjee, N. (Nilanjana), Baras, A. (Aris), Barnard, L. (Leland), Beechert, C. (Christina), Blumenfeld, A. (Andrew), Cantor, M. (Michael), Chai, Y. (Yating), Coppola, G. (Giovanni), Damask, A. (Amy), Dewey, F. (Frederick), Economides, A. (Aris), Eom, G. (Gisu), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Gurski, L. (Lauren), Guzzardo, P.M. (Paloma M.), Habegger, L. (Lukas), Hahn, Y. (Young), Hawes, A. (Alicia), van Hout, C. (Cristopher), Jones, M.B. (Marcus B.), Khalid, S. (Shareef), Lattari, M. (Michael), Li, A. (Alexander), Lin, N. (Nan), Liu, D. (Daren), Lopez, A. (Alexander), Manoochehri, K. (Kia), Marchini, J. (Jonathan), Marcketta, A. (Anthony), Maxwell, E.K. (Evan K.), McCarthy, S. (Shane), Mitnaul, L.J. (Lyndon), O’Dushlaine, C. (Colm), Overton, J.D. (John D.), Padilla, M.S. (Maria Sotiropoulos), Paulding, C. (Charles), Penn, J. (John), Pradhan, M. (Manasi), Reid, J.G. (Jeffrey G.), Schleicher, T.D. (Thomas D.), Schurmann, C. (Claudia), Shuldiner, A. (Alan), Staples, J.C. (Jeffrey C.), Sun, D. (Dylan), Toledo, K. (Karina), Ulloa, R.H. (Ricardo H.), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Yadav, A. (Ashish), Ye, B. (Bin), Rice, K.M. (Kenneth), Ridker, P.M. (Paul M.), Romaine, S.P.R. (Simon P. R.), Rotter, J.I. (Jerome I.), Salo, P. (Perttu), Salomaa, V. (Veikko), Setten, J. (Jessica) van, Shalaby, A.A. (Alaa A.), Smelser, D.T. (Diane T.), Smith, N.L. (Nicholas L.), Stender, S. (Steen), Stott, D.J. (David. J.), Svensson, P. (Per), Tammesoo, M.L., Taylor, K.D. (Kent D.), Teder-Laving, M. (Maris), Teumer, A. (Alexander), Thorgeirsson, G. (Guðmundur), Thorsteinsdottir, U. (Unnur), Torp-Pedersen, C. (Christian Tobias), Trompet, S. (Stella), Tyl, B. (Benoit), Uitterlinden, A.G. (Andre G.), Veluchamy, A. (Abirami), Völker, U. (Uwe), Voors, A.A. (Adriaan A.), Wang, X. (Xiaosong), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Weeke, P.E. (Peter E.), Weiss, R. (Ram), Wiggins, K.L. (Kerri L.), Xing, H. (Heming), Yerges-Armstrong, L.M. (Laura), Yu, B. (Bing), Zannad, F. (Faiez), Zhao, J.H. (Jing Hua), Hemingway, H., Samani, N.J. (Nilesh J.), McMurray, J.J.V. (John J. V.), Yang, J. (Jian), Visscher, P.M. (Peter M.), Newton-Cheh, C. (Christopher), Mälarstig, A. (Anders), Holm, H. (Hilma), Lubitz, S.A. (Steven), Sattar, N. (Naveed), Holmes, M.V. (Michael), Cappola, T.P. (Thomas P.), Asselbergs, F.W. (Folkert), Hingorani, A. (Aroon), Kuchenbaecker, K.B. (Karoline), Ellinor, P.T. (Patrick), Lang, C.C. (Chim C.), Stefansson, K. (Kari), Smith, J.G. (J Gustav), Vasan, R.S. (Ramachandran Srini), Swerdlow, D.I. (Daniel), and Lumbers, R.T. (R. Thomas)
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
Published: 2020
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11. Temporal Pattern of Growth Differentiation Factor-15 Protein After Acute Coronary Syndrome (From the BIOMArCS Study)

Author: Buljubasic, N. (Nermina), Vroegindewey, M.M. (Maxime), Oemrawsingh, R.M. (Rohit), Asselbergs, F.W. (Folkert), Cramer, E., Liem, A, Harst, P. (Pim) van der, Maas, A. (Arne), Ronner, E. (Eelko), Schotborgh, C., Wardeh, A.J. (Alexander), Akkerhuis, K.M. (Martijn), Boersma, H. (Eric), Buljubasic, N. (Nermina), Vroegindewey, M.M. (Maxime), Oemrawsingh, R.M. (Rohit), Asselbergs, F.W. (Folkert), Cramer, E., Liem, A, Harst, P. (Pim) van der, Maas, A. (Arne), Ronner, E. (Eelko), Schotborgh, C., Wardeh, A.J. (Alexander), Akkerhuis, K.M. (Martijn), and Boersma, H. (Eric)
Abstract: Growth differentiation factor-15 (GDF-15) has appeared as a promising biomarker with strong predictive abilities in acute coronary syndrome (ACS). However, studies are solely based on single measurements in the acute phase of an ACS event. The way GDF-15 patterns in post-ACS patients behave on the long term is largely unknown. We conducted a nested case-control study within our multicenter, prospective, observational biomarker study (BIOMArCS) of 844 ACS patients. Following an index ACS event, high-frequency blood sampling was performed during 1-year of follow-up. GDF-15 was determined batchwise by electrochemiluminescence immunoassays in 37 cases with a recurrent event during 1-year follow-up, and in 74 event-free controls. Cases and controls had a mean § standard deviation age of 66.9 § 11.3 years and 81% were men. From 30 days onwards, patients showed stable levels, which were on average 333 (95% confidence interval 68 to 647) pg/mL higher in cases than controls (1704 vs 1371 pg/mL; p value 0.013). Additionally, in the post 30-day period, GDF-15 showed low within-individual variability in both cases and controls. In conclusion, post-ACS patients experiencing a recurrent event had stable and systematically higher GDF-15 levels during 30-day to 1-year follow-up than their event-free counterparts with otherwise similar clinical characteristics. Thus, postdischarge blood sampling might be used throughout the course of 1 year to improve prognostication, whereas, in view of the low within-individual variation, the number of repeated sampling moments might be limited.
Published: 2019
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12. Details on high frequency blood collection, data analysis, available material and patient characteristics in BIOMArCS

Author: Boersma, H. (Eric), Vroegindewey, M.M. (Maxime), van den Berg, V.J., Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Kietselaer, B., Lenderink, T, Oude Ophuis, A.J.M. (Anthonius), Umans, V.A.W.M. (Victor), Winter, R.J. de, Oemrawsingh, R.M. (Rohit), Akkerhuis, K.M. (Martijn), Boersma, H. (Eric), Vroegindewey, M.M. (Maxime), van den Berg, V.J., Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Kietselaer, B., Lenderink, T, Oude Ophuis, A.J.M. (Anthonius), Umans, V.A.W.M. (Victor), Winter, R.J. de, Oemrawsingh, R.M. (Rohit), and Akkerhuis, K.M. (Martijn)
Abstract: The Biomarker Study to Identify the Acute Risk of a Coronary Syndrome (BIOMArCS) is a prospective, observational study that has been designed to study the evolution of blood biomarkers in post-acute coronary syndrome (ACS) patients. In our recently published study “Temporal evolution of Myeloperoxidase and Galect
Published: 2019
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13. Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome: BIOMArCS study

Author: Brankovic, M. (Milos), Kardys, I. (Isabella), van den Berg, V.J. (Victor J.), Oemrawsingh, R.M. (Rohit), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Hoefer, I.E. (Imo), Liem, A.H. (Anho), Maas, A.C.P. (Arthur), Ronner, E. (Eelko), Schotborgh, C., The, S.H.K. (S. Hong Kie), Hoorn, E.J. (Ewout), Boersma, H. (Eric), Akkerhuis, K.M. (Martijn), Brankovic, M. (Milos), Kardys, I. (Isabella), van den Berg, V.J. (Victor J.), Oemrawsingh, R.M. (Rohit), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Hoefer, I.E. (Imo), Liem, A.H. (Anho), Maas, A.C.P. (Arthur), Ronner, E. (Eelko), Schotborgh, C., The, S.H.K. (S. Hong Kie), Hoorn, E.J. (Ewout), Boersma, H. (Eric), and Akkerhuis, K.M. (Martijn)
Abstract: Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: Fr
Published: 2019
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14. Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium

Author: Bahls, M. (Martin), Lorenz, M.W. (Matthias W.), Dörr, M. (Marcus), Gao, L. (Lu), Kitagawa, K. (Kazuo), Tuomainen, T.-P. (Tomi-Pekka), Agewall, S. (Stefan), Berenson, G. (Gerald), Catapano, A.L. (Alberico), Norata, G.D. (Giuseppe), Bots, M.L. (Michiel), Gilst, W.H. (Wiek) van, Asselbergs, F.W. (Folkert), Brouwers, F.P. (Frank P), Uthoff, H. (Heiko), Sander, D. (Dirk), Poppert, H. (Holger), Hecht Olsen, M. (Michael), Empana, J.P. (Jean Philippe), Schminke, U. (Ulf), Baldassarre, D. (Damiano), Veglia, F. (Fabrizio), Franco, O.H. (Oscar), Kavousi, M. (Maryam), Groot, E. (Eric) de, Mathiesen, E.B. (Ellisiv), Grigore, L. (Liliana), Polak, J. (Joseph), Rundek, T. (Tatjana), Stehouwer, C.D. (Coen), Skilton, M.R. (Michael R), Hatzitolios, A.I. (Apostolos I), Savopoulos, C. (Christos), Ntaios, G. (George), Plichart, M. (Matthieu), McLachlan, S. (Stela), Kao, W.H.L. (Wen), Willeit, P. (Peter), Steinmetz, H. (Helmuth), Desvarieux, M. (Moise), Ikram, M.A. (Arfan), Johnsen, S.H., Schmidt, C. (Caroline), Willeit, J. (Johann), Ducimetiere, P. (P.), Price, J.F. (Jackie F), Bergström, G. (Göran), Kauhanen, J. (Jussi), Kiechl, S. (Stefan), Sitzer, M. (Matthias), Bickel, H. (Horst), Muir, K.W. (Keith), Hofman, A. (Albert), Völzke, H. (Henry), Thompson, S.G. (Simon G), Bahls, M. (Martin), Lorenz, M.W. (Matthias W.), Dörr, M. (Marcus), Gao, L. (Lu), Kitagawa, K. (Kazuo), Tuomainen, T.-P. (Tomi-Pekka), Agewall, S. (Stefan), Berenson, G. (Gerald), Catapano, A.L. (Alberico), Norata, G.D. (Giuseppe), Bots, M.L. (Michiel), Gilst, W.H. (Wiek) van, Asselbergs, F.W. (Folkert), Brouwers, F.P. (Frank P), Uthoff, H. (Heiko), Sander, D. (Dirk), Poppert, H. (Holger), Hecht Olsen, M. (Michael), Empana, J.P. (Jean Philippe), Schminke, U. (Ulf), Baldassarre, D. (Damiano), Veglia, F. (Fabrizio), Franco, O.H. (Oscar), Kavousi, M. (Maryam), Groot, E. (Eric) de, Mathiesen, E.B. (Ellisiv), Grigore, L. (Liliana), Polak, J. (Joseph), Rundek, T. (Tatjana), Stehouwer, C.D. (Coen), Skilton, M.R. (Michael R), Hatzitolios, A.I. (Apostolos I), Savopoulos, C. (Christos), Ntaios, G. (George), Plichart, M. (Matthieu), McLachlan, S. (Stela), Kao, W.H.L. (Wen), Willeit, P. (Peter), Steinmetz, H. (Helmuth), Desvarieux, M. (Moise), Ikram, M.A. (Arfan), Johnsen, S.H., Schmidt, C. (Caroline), Willeit, J. (Johann), Ducimetiere, P. (P.), Price, J.F. (Jackie F), Bergström, G. (Göran), Kauhanen, J. (Jussi), Kiechl, S. (Stefan), Sitzer, M. (Matthias), Bickel, H. (Horst), Muir, K.W. (Keith), Hofman, A. (Albert), Völzke, H. (Henry), and Thompson, S.G. (Simon G)
Abstract: Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in
Published: 2019
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15. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), Wilson, J.F. (James), Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), and Wilson, J.F. (James)
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019
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16. A randomised comparison of the effect of haemodynamic monitoring with CardioMEMS in addition to standard care on quality of life and hospitalisations in patients with chronic heart failure: Design and rationale of the MONITOR HF multicentre randomised clinical trial

Author: Brugts, J.J. (Jasper), Veenis, J.F. (Jesse), Radhoe, S.P. (Sumant), Linssen, G.C.M. (Gerard), van Gent, M. (M.), Borleffs, C.J.W. (Jan Willem), Ramshorst, J. (Jan) van, Pol, P.E.J. (Petra) van, Tukkie, R. (Raymond), Spee, R.F. (R. F.), Emans, M.E. (M. E.), Kok, W.E.M. (Wouter), Halm, V.P. (V.) van, Handoko, L. (L.), Beeres, S.L.M.A. (Saskia), Post, M.C. (Martijn), Boersma, H. (Eric), Lenzen, M.J. (Mattie), Manintveld, O.C. (Olivier), Koffijberg, H. (Hendrik), Baal, P.H.M. (Pieter) van, Versteegh, M.M. (Matthijs), Smilde, T.D. (Tom), Van Heerebeek, L. (Loek), Rienstra, S.A., Mosterd, A. (Arend), Delnoy, P.P.H. (P. P.H.), Asselbergs, F.W. (Folkert), Brunner La Rocca, H.P. (Hans Peter), Boer, R.A. (Rudolf) de, Brugts, J.J. (Jasper), Veenis, J.F. (Jesse), Radhoe, S.P. (Sumant), Linssen, G.C.M. (Gerard), van Gent, M. (M.), Borleffs, C.J.W. (Jan Willem), Ramshorst, J. (Jan) van, Pol, P.E.J. (Petra) van, Tukkie, R. (Raymond), Spee, R.F. (R. F.), Emans, M.E. (M. E.), Kok, W.E.M. (Wouter), Halm, V.P. (V.) van, Handoko, L. (L.), Beeres, S.L.M.A. (Saskia), Post, M.C. (Martijn), Boersma, H. (Eric), Lenzen, M.J. (Mattie), Manintveld, O.C. (Olivier), Koffijberg, H. (Hendrik), Baal, P.H.M. (Pieter) van, Versteegh, M.M. (Matthijs), Smilde, T.D. (Tom), Van Heerebeek, L. (Loek), Rienstra, S.A., Mosterd, A. (Arend), Delnoy, P.P.H. (P. P.H.), Asselbergs, F.W. (Folkert), Brunner La Rocca, H.P. (Hans Peter), and Boer, R.A. (Rudolf) de
Abstract: Background: Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. Aims: To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. Methods: The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including health
Published: 2019
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17. The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update

Author: Bosman, L.P. (L. P.), Verstraelen, T.E. (T. E.), van Lint, F.H.M. (F. H.M.), Cox, M.G.P.J. (Moniek), Groeneweg, J.A. (Judith), Mast, T.P. (T. P.), Zwaag, P.A. (Paul) van der, Volders, P.G.A. (Paul), Evertz, R. (Reinder), Wong, L. (L.), Groot, N.M.S. (Natasja) de, Zeppenfeld, K. (Katja), Heijden, J.F. (Jeroen) van der, Berg, M.P. (Maarten) van den, Wilde, A.A.M. (Arthur), Asselbergs, F.W. (Folkert), Hauer, R.N.W. (Richard), Riele, A.S. (Anneline) te, van Tintelen, J.P. (J. P.), Baas, A.F. (A. F.), Barge-Schaapveld, D.Q.C.M. (Daniela), Boekholdt, S.M. (Matthijs), Cramer, M.J.M. (M. J.M.), Dooijes, D. (D.), Jongbloed, J.D.H. (Jan), Loh, P. (Peter), Planken, R.N. (R. N.), Prakken, N.H.J. (N. H.J.), Smagt, J.J. (Jasper) van der, van der Wal, A.C. (A. C.), Teske, A.J. (A. J.), Veen, T.A.B. (Toon) van, Velthuis, B.K. (Birgitta), Vink, A. (Ard), Yap, S.C. (S. C.), Bosman, L.P. (L. P.), Verstraelen, T.E. (T. E.), van Lint, F.H.M. (F. H.M.), Cox, M.G.P.J. (Moniek), Groeneweg, J.A. (Judith), Mast, T.P. (T. P.), Zwaag, P.A. (Paul) van der, Volders, P.G.A. (Paul), Evertz, R. (Reinder), Wong, L. (L.), Groot, N.M.S. (Natasja) de, Zeppenfeld, K. (Katja), Heijden, J.F. (Jeroen) van der, Berg, M.P. (Maarten) van den, Wilde, A.A.M. (Arthur), Asselbergs, F.W. (Folkert), Hauer, R.N.W. (Richard), Riele, A.S. (Anneline) te, van Tintelen, J.P. (J. P.), Baas, A.F. (A. F.), Barge-Schaapveld, D.Q.C.M. (Daniela), Boekholdt, S.M. (Matthijs), Cramer, M.J.M. (M. J.M.), Dooijes, D. (D.), Jongbloed, J.D.H. (Jan), Loh, P. (Peter), Planken, R.N. (R. N.), Prakken, N.H.J. (N. H.J.), Smagt, J.J. (Jasper) van der, van der Wal, A.C. (A. C.), Teske, A.J. (A. J.), Veen, T.A.B. (Toon) van, Velthuis, B.K. (Birgitta), Vink, A. (Ard), and Yap, S.C. (S. C.)
Abstract: Background: Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. Aim: To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. Methods: This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. Discussion: The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website (www.acmregistry.nl) and patient conferences.
Published: 2019
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18. Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1

Author: Pei, J. (Jiayi), Juni, R.P. (Rio), Harakalova, M. (Magdalena), Duncker, D.J.G.M. (Dirk), Asselbergs, F.W. (Folkert), Koolwijk, P. (Pieter), Hinsbergh, V.W.M. (Victor) van, Verhaar, M.C. (Marianne), Mokry, M. (Michal), Cheng, C. (Caroline), Pei, J. (Jiayi), Juni, R.P. (Rio), Harakalova, M. (Magdalena), Duncker, D.J.G.M. (Dirk), Asselbergs, F.W. (Folkert), Koolwijk, P. (Pieter), Hinsbergh, V.W.M. (Victor) van, Verhaar, M.C. (Marianne), Mokry, M. (Michal), and Cheng, C. (Caroline)
Abstract: Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in human umbilical vein endothelial cells (HUVECs) after IS or control medium treatment and identified 1293 genes that were affected in a IS-induced response. Gene enrichment analysis highlighted pathways involved in altered vascular formation and cell metabolism. We confirmed these transcriptome profiles at the functional level by demonstrating decreased viability and increased cell senescence in response to IS treatment. In line with the additional pathways highlighted by the transcriptome analysis, we further could demonstrate that IS exposure of HUVECs promoted tubule formation as shown by the increase in total tubule length in a 3D HUVECs/pericytes co-culture assay. Notably, the pro-angiogenic response of IS and increased ROS production were abolished when CYP1B1, one of the main target genes that was highly upregulated by IS, was silenced. This observation indicates IS-induced ROS in endothelial cells is CYP1B1-dependent. Taken together, our findings demonstrate that IS promotes angiogenesis and CYP1B1 is an important factor in IS-activated angiogenic response.
Published: 2019
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19. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy

Author: Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Nozza, A. (Anna), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Fortier, A. (Annik), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Heijden, J.F. (Jeroen) van der, Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), Guertin, M.-C. (Marie-Claude), Tintelen, J.P. (Peter) van, Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, James, C.A. (Cynthia), Cadrin-Tourigny, J. (Julia), Bosman, L.P. (Laurens P.), Nozza, A. (Anna), Wang, W. (Weijia), Tadros, R. (Rafik), Bhonsale, A. (Aditya), Bourfiss, M. (Mimount), Fortier, A. (Annik), Lie, ØH. (Øyvind H), Saguner, A.M. (Ardan M.), Svensson, A. (Anneli), Andorin, A. (Antoine), Tichnell, C. (Crystal), Murray, B. (Brittney), Zeppenfeld, K. (Katja), Berg, M.P. (Maarten) van den, Asselbergs, F.W. (Folkert), Wilde, A.A.M. (Arthur), Krahn, A.D. (Andrew D.), Talajic, M. (Mario), Rivard, L. (Lena), Chelko, S. (Stephen), Zimmerman, S.L. (Stefan), Kamel, M.S. (Mohamed), Crosson, J.E. (Jane E.), Judge, D.P. (Daniel), Yap, S.-C. (Sing-Chien), Heijden, J.F. (Jeroen) van der, Tandri, H. (Harikrishna), Jongbloed, J.D.H. (Jan), Guertin, M.-C. (Marie-Claude), Tintelen, J.P. (Peter) van, Platonov, P.G. (Pyotr G.), Duru, F. (Firat), Haugaa, K.H. (Kristina H.), Khairy, P. (Paul), Hauer, R.N.W. (Richard), Calkins, H. (Hugh), Riele, A.S. (Anneline) te, and James, C.A. (Cynthia)
Abstract: AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).
Published: 2019
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20. Increasing sensitivityacommon-sense approach?

Author: Michels, M. (Michelle), Asselbergs, F.W. (Folkert), Velden, J., Michels, M. (Michelle), Asselbergs, F.W. (Folkert), and Velden, J.
Published: 2019
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21. The temporal pattern of immune and inflammatory proteins prior to a recurrent coronary event in post-acute coronary syndrome patients

Author: Vroegindewey, M.M. (Maxime), Oemrawsingh, R.M. (Rohit), Kardys, I. (Isabella), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Oude Ophuis, A.J.M. (Anthonius), Cramer, G.E., Maas, A. (Arne), The, SHK, Wardeh, A.J. (Alexander), Mouthaan, H., Boersma, H. (Eric), Akkerhuis, K.M. (Martijn), Vroegindewey, M.M. (Maxime), Oemrawsingh, R.M. (Rohit), Kardys, I. (Isabella), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Oude Ophuis, A.J.M. (Anthonius), Cramer, G.E., Maas, A. (Arne), The, SHK, Wardeh, A.J. (Alexander), Mouthaan, H., Boersma, H. (Eric), and Akkerhuis, K.M. (Martijn)
Abstract: Purpose: We assessed the temporal pattern of 29 immune and inflammatory proteins in post-acute coronary syndrome (ACS) patients, prior to the development of recurrent ACS. Methods: High-frequency blood sampling was performed in 844 patients admitted for ACS during one-year follow-up. We conducted a case-control study on the 45 patients who experienced reACS (cases) and two matched event-free patients (controls) per case. Olink Proteomics’ immunoassay was used to obtain serum levels of the 29 proteins, expressed in an arbitrary unit on the log2-scale (Normalized Protein eXpression, NPX). Linear mixed-effects models were applied to examine the temporal pattern of the proteins, and to illustrate differences between cases and controls. Results: Mean age was 66 ± 12 years and 80% were men. Cases and controls had similar baseline clinical characteristics. During the first 30 days, and after multiple testing correction, cases had significantly higher serum levels of CXCL1 (difference of 1.00 NPX, p ¼ 0.002), CD84 (difference of 0.64 NPX, p ¼ 0.002) and TNFRSF10A (difference of 0.41 NPX, p < 0.001) than controls. After 30 days, serum levels of all 29 proteins were similar in cases and controls. In particular, no increase was observed prior to reACS. Conclusions: Among 29 immune and inflammatory proteins, CXCL1, CD84 and TNFRSF10A were associated with early reACS after initial ACS-admission.
Published: 2019
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22. Subsequent Event Risk in Individuals With Established Coronary Heart Disease

Author: Patel, R.S. (Riyaz), Tragante, V. (Vinicius), Schmidt, A.F. (Amand), McCubrey, R.O. (Raymond O.), Holmes, M.V. (Michael), Howe, L.J. (Laurence J.), Direk, K. (Kenan), Åkerblom, A. (Axel), Leander, K. (Karin), Virani, S.S. (Salim), Kaminski, K.A. (Karol A.), Muehlschlegel, J.D. (Jochen), Allayee, H. (Hooman), Almgren, P. (Peter), Alver, M. (Maris), Baranova, E.V. (Ekaterina V.), Behloui, H. (Hassan), Boeckx, B. (Bram), Braund, P.S. (Peter), Breitling, L.P. (Lutz), Delgado, G., Duarte, N.E. (Nubia E.), Dubé, G.P. (Gregory), Dufresne, L. (Line), Eriksson, N. (Niclas), Foco, L. (Luisa), Scholz, M. (Markus), Gijsberts, C.M. (Crystel M.), Glinge, C. (Charlotte), Gong, Y. (Yan), Hartiala, J. (Jaana), Heydarpour, M. (Mahyar), Hubacek, J.A. (Jaroslav A.), Kleber, M.E. (Marcus), Kofink, D. (Daniel), Kotti, S. (Salma), Kuukasjärvi, P. (Pekka), Lee, V.-V. (Vei-Vei), Leiherer, A. (Andreas), Lenzini, P.A. (Petra A.), Levin, D. (Daniel), Lyytikäinen, L.-P. (Leo-Pekka), Martinelli, N. (Nicola), Mons, U. (Ute), Nelson, C.P. (Christopher P.), Nikus, K. (Kjell), Pilbrow, A.P. (Anna P.), Ploski, R. (Rafal), Sun, Y.V. (Yan V.), Tanck, M.W.T. (Michael), Tang, W. (W.), Trompet, S. (Stella), van der Laan, S.W. (Sander W.), Setten, J. (Jessica) van, Vilmundarson, R.O. (Ragnar O.), Viviani Anselmi, C. (Chiara), Vlachopoulou, E. (Efthymia), Al Ali, L. (Lawien), Boerwinkle, E.A. (Eric), Briguori, C. (Carlo), Carlquist, J.F. (John), Carruthers, K.F. (Kathryn), Casu, G. (Gavino), Deanfield, J. (John), Deloukas, P. (Panos), Dudbridge, F. (Frank), Engstrøm, T. (Thomas), Fitzpatrick, N. (Natalie), Fox, K.M. (Kim), Gigante, B. (Bruna), James, S.K. (Stefan), Lokki, M.-L. (Marja-Liisa), Lotufo, P.A. (Paulo A.), Marziliano, N. (Nicola), Mordi, I.R. (Ify R.), Muhlestein, J.B. (Joseph), Newton-Cheh, C. (Christopher), Pitha, J. (Jan), Saely, C.H. (Christoph H.), Samman-Tahhan, A. (Ayman), Sandesara, P.B. (Pratik B.), Teren, A. (Andrej), Timmis, A. (Adam), Van de Werf, F. (Frans), Wilde, A.A.M. (Arthur), Ford, I. (Ian), Stott, D.J. (David. J.), Algra, A. (Ale), Andreassi, M.G. (Maria G.), Ardissino, D. (Diego), Arsenault, B.J. (Benoit J.), Ballantyne, C. (Christie), Bergmeijer, T.O. (Thomas O.), Bezzina, C.R. (Connie R.), Body, S.C. (Simon C.), Boersma, E.H. (Eric H.), Bogaty, P. (Peter), Bots, M.L. (Michiel), Brenner, H. (Hermann), Brugts, J.J. (Jasper), Burkhardt, R. (Ralph), Carpeggiani, C. (Clara), Condorelli, G. (Gianluigi), Cooper-Dehoff, R.M. (Rhonda), Cresci, S. (Sharon), Danchin, N. (Nicolas), Faire, U. (Ulf) de, Doughty, R.N. (Robert N.), Drexel, H. (Heinz), Engert, J.C. (James C.), Fox, K.A.A. (Keith), Girelli, D. (Domenico), Grobbee, D.E. (Diederick E.), Hagström, E. (Emil), Hazen, S.L. (Stanley), Held, C. (Claes), Hemingway, H., Hoefer, I.E. (Imo), Hovingh, G.K. (G Kees), Jabbari, R. (Reza), Johnson, J.A. (Jennifer ), Jukema, J.W. (Jan Wouter), Kaczor, M.P. (Marcin P.), Kähönen, M. (Mika), Kettner, J. (Jiri), Kiliszek, M. (Marek), Klungel, O.H. (Olaf), Lagerqvist, B. (Bo), Lambrechts, D. (Diether), Laurikka, J.O. (Jari O.), Lehtimäki, T. (Terho), Lindholm, D. (Daniel), Mahmoodi, B.K. (Bakhtawar K.), Maitland-van der Zee, A-H. (Anke-Hilse), McPherson, R. (Ruth), Melander, O. (Olle), Metspalu, A. (Andres), Niemcunowicz-Janica, A. (Anna), Olivieri, O. (Oliviero), Opolski, G. (Grzegorz), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Pepine, C.J. (Carl), Pereira, A. (A.), Pilote, L. (Louise), Erdmann, J. (Jeanette), Richards, A.M. (A Mark), Sanak, M. (Marek), Siegbahn, A. (Agneta), Simon, T. (Tabassome), Sinisalo, J. (Juha), Smith, J.G. (J Gustav), Schwartz, S.M. (Stephen), Stender, S. (Steen), Stewart, A.F. (Alexandre F.), Szczeklik, W. (Wojciech), Szpakowicz, A. (Anna), Tardif, J.-C. (Jean-Claude), Berg, J.M. (Jurrien) ten, Tfelt-Hansen, J. (Jacob), Thanassoulis, G. (George), Thiery, J.P. (Joachim), Torp-Pedersen, C. (Christian Tobias), Graaf, Y. (Yolanda) van der, Visseren, F.L.J. (Frank), Waltenberger, J. (Johannes), Weeke, P.E. (Peter E.), Harst, P. (Pim) van der, Lang, C.C. (Chim C.), Sattar, N. (Naveed), Cameron, V.A. (Vicky A.), Anderson, J.L. (Jeffrey), Brophy, J.M. (James M.), Pare, G. (Guillame), Horne, B.D. (Benjamin), Ye, S. (Shu), Wallentin, L. (Lars), Wauters, E. (Els), Samani, N.J. (Nilesh), Hingorani, A. (Aroon), Asselbergs, F.W. (Folkert), Patel, R.S. (Riyaz), Tragante, V. (Vinicius), Schmidt, A.F. (Amand), McCubrey, R.O. (Raymond O.), Holmes, M.V. (Michael), Howe, L.J. (Laurence J.), Direk, K. (Kenan), Åkerblom, A. (Axel), Leander, K. (Karin), Virani, S.S. (Salim), Kaminski, K.A. (Karol A.), Muehlschlegel, J.D. (Jochen), Allayee, H. (Hooman), Almgren, P. (Peter), Alver, M. (Maris), Baranova, E.V. (Ekaterina V.), Behloui, H. (Hassan), Boeckx, B. (Bram), Braund, P.S. (Peter), Breitling, L.P. (Lutz), Delgado, G., Duarte, N.E. (Nubia E.), Dubé, G.P. (Gregory), Dufresne, L. (Line), Eriksson, N. (Niclas), Foco, L. (Luisa), Scholz, M. (Markus), Gijsberts, C.M. (Crystel M.), Glinge, C. (Charlotte), Gong, Y. (Yan), Hartiala, J. (Jaana), Heydarpour, M. (Mahyar), Hubacek, J.A. (Jaroslav A.), Kleber, M.E. (Marcus), Kofink, D. (Daniel), Kotti, S. (Salma), Kuukasjärvi, P. (Pekka), Lee, V.-V. (Vei-Vei), Leiherer, A. (Andreas), Lenzini, P.A. (Petra A.), Levin, D. (Daniel), Lyytikäinen, L.-P. (Leo-Pekka), Martinelli, N. (Nicola), Mons, U. (Ute), Nelson, C.P. (Christopher P.), Nikus, K. (Kjell), Pilbrow, A.P. (Anna P.), Ploski, R. (Rafal), Sun, Y.V. (Yan V.), Tanck, M.W.T. (Michael), Tang, W. (W.), Trompet, S. (Stella), van der Laan, S.W. (Sander W.), Setten, J. (Jessica) van, Vilmundarson, R.O. (Ragnar O.), Viviani Anselmi, C. (Chiara), Vlachopoulou, E. (Efthymia), Al Ali, L. (Lawien), Boerwinkle, E.A. (Eric), Briguori, C. (Carlo), Carlquist, J.F. (John), Carruthers, K.F. (Kathryn), Casu, G. (Gavino), Deanfield, J. (John), Deloukas, P. (Panos), Dudbridge, F. (Frank), Engstrøm, T. (Thomas), Fitzpatrick, N. (Natalie), Fox, K.M. (Kim), Gigante, B. (Bruna), James, S.K. (Stefan), Lokki, M.-L. (Marja-Liisa), Lotufo, P.A. (Paulo A.), Marziliano, N. (Nicola), Mordi, I.R. (Ify R.), Muhlestein, J.B. (Joseph), Newton-Cheh, C. (Christopher), Pitha, J. (Jan), Saely, C.H. (Christoph H.), Samman-Tahhan, A. (Ayman), Sandesara, P.B. (Pratik B.), Teren, A. (Andrej), Timmis, A. (Adam), Van de Werf, F. (Frans), Wilde, A.A.M. (Arthur), Ford, I. (Ian), Stott, D.J. (David. J.), Algra, A. (Ale), Andreassi, M.G. (Maria G.), Ardissino, D. (Diego), Arsenault, B.J. (Benoit J.), Ballantyne, C. (Christie), Bergmeijer, T.O. (Thomas O.), Bezzina, C.R. (Connie R.), Body, S.C. (Simon C.), Boersma, E.H. (Eric H.), Bogaty, P. (Peter), Bots, M.L. (Michiel), Brenner, H. (Hermann), Brugts, J.J. (Jasper), Burkhardt, R. (Ralph), Carpeggiani, C. (Clara), Condorelli, G. (Gianluigi), Cooper-Dehoff, R.M. (Rhonda), Cresci, S. (Sharon), Danchin, N. (Nicolas), Faire, U. (Ulf) de, Doughty, R.N. (Robert N.), Drexel, H. (Heinz), Engert, J.C. (James C.), Fox, K.A.A. (Keith), Girelli, D. (Domenico), Grobbee, D.E. (Diederick E.), Hagström, E. (Emil), Hazen, S.L. (Stanley), Held, C. (Claes), Hemingway, H., Hoefer, I.E. (Imo), Hovingh, G.K. (G Kees), Jabbari, R. (Reza), Johnson, J.A. (Jennifer ), Jukema, J.W. (Jan Wouter), Kaczor, M.P. (Marcin P.), Kähönen, M. (Mika), Kettner, J. (Jiri), Kiliszek, M. (Marek), Klungel, O.H. (Olaf), Lagerqvist, B. (Bo), Lambrechts, D. (Diether), Laurikka, J.O. (Jari O.), Lehtimäki, T. (Terho), Lindholm, D. (Daniel), Mahmoodi, B.K. (Bakhtawar K.), Maitland-van der Zee, A-H. (Anke-Hilse), McPherson, R. (Ruth), Melander, O. (Olle), Metspalu, A. (Andres), Niemcunowicz-Janica, A. (Anna), Olivieri, O. (Oliviero), Opolski, G. (Grzegorz), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Pepine, C.J. (Carl), Pereira, A. (A.), Pilote, L. (Louise), Erdmann, J. (Jeanette), Richards, A.M. (A Mark), Sanak, M. (Marek), Siegbahn, A. (Agneta), Simon, T. (Tabassome), Sinisalo, J. (Juha), Smith, J.G. (J Gustav), Schwartz, S.M. (Stephen), Stender, S. (Steen), Stewart, A.F. (Alexandre F.), Szczeklik, W. (Wojciech), Szpakowicz, A. (Anna), Tardif, J.-C. (Jean-Claude), Berg, J.M. (Jurrien) ten, Tfelt-Hansen, J. (Jacob), Thanassoulis, G. (George), Thiery, J.P. (Joachim), Torp-Pedersen, C. (Christian Tobias), Graaf, Y. (Yolanda) van der, Visseren, F.L.J. (Frank), Waltenberger, J. (Johannes), Weeke, P.E. (Peter E.), Harst, P. (Pim) van der, Lang, C.C. (Chim C.), Sattar, N. (Naveed), Cameron, V.A. (Vicky A.), Anderson, J.L. (Jeffrey), Brophy, J.M. (James M.), Pare, G. (Guillame), Horne, B.D. (Benjamin), Ye, S. (Shu), Wallentin, L. (Lars), Wauters, E. (Els), Samani, N.J. (Nilesh), Hingorani, A. (Aroon), and Asselbergs, F.W. (Folkert)
Abstract: BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants a
Published: 2019
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23. The temporal pattern of immune and inflammatory proteins prior to a recurrent coronary event in post-acute coronary syndrome patients

Author: Vroegindewey, M.M. (Maxime), Oemrawsingh, R.M. (Rohit), Kardys, I. (Isabella), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Oude Ophuis, A.J.M. (Anthonius), Etienne Cramer, G. (G.), Maas, A.C.P. (Arthur), Hong Kie The, S. (S.), Wardeh, A.J. (Alexander), Mouthaan, H. (Henk), Boersma, H. (Eric), Akkerhuis, K.M. (Martijn), Vroegindewey, M.M. (Maxime), Oemrawsingh, R.M. (Rohit), Kardys, I. (Isabella), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Oude Ophuis, A.J.M. (Anthonius), Etienne Cramer, G. (G.), Maas, A.C.P. (Arthur), Hong Kie The, S. (S.), Wardeh, A.J. (Alexander), Mouthaan, H. (Henk), Boersma, H. (Eric), and Akkerhuis, K.M. (Martijn)
Abstract: Purpose: We assessed the temporal pattern of 29 immune and inflammatory proteins in post-acute coronary syndrome (ACS) patients, prior to the development of recurrent ACS. Methods: High-frequency blood sampling was performed in 844 patients admitted for ACS during one-year follow-up. We conducted a case-control study on the 45 patients who experienced reACS (cases) and two matched event-free patients (controls) per case. Olink Proteomics’ immunoassay was used to obtain serum levels of the 29 proteins, expressed in an arbitrary unit on the log2-scale (Normalized Protein eXpression, NPX). Linear mixed-effects models were applied to examine the temporal pattern of the proteins, and to illustrate differences between cases and controls. Results: Mean age was 66 ± 12 years and 80% were men. Cases and controls had similar baseline clinical characteristics. During the first 30 days, and after multiple testing correction, cases had significantly higher serum levels of CXCL1 (difference of 1.00 NPX, p = 0.002), CD84 (difference of 0.64 NPX, p = 0.002) and TNFRSF10A (difference of 0.41 NPX, p < 0.001) than controls. After 30 days, serum levels of all 29 proteins were similar in cases and controls. In particular, no increase was observed prior to reACS. Conclusions: Among 29 immune and inflammatory proteins, CXCL1, CD84 and TNFRSF10A were associated with early reACS after initial ACS-admission.
Published: 2018
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24. ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Author: Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Albert), Warren, H. (Helen), Lin, H. (Honghuang), Isaacs, A. (Aaron), Liu, C.-T. (Ching-Ti), Marten, J. (Jonathan), Radmanesh, F. (Farid), Hall, L.M. (Leanne M.), Grarup, N. (Niels), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Huffman, J.E. (Jennifer E.), Verweij, N. (Niek), Guo, X. (Xiuqing), Yao, J. (Jie), Li-Gao, R. (Ruifang), Berg, M.E. (Marten) van den, Weiss, S. (Stefan), Prins, B.P. (Bram P.), Setten, J. (Jessica) van, Haessler, J. (Jeff), Lyytikäinen, L.-P. (Leo-Pekka), Li, M. (Man), Alonso, A. (Alvaro), Soliman, E.Z. (Elsayed Z.), Bis, J.C. (Joshua), Austin, T. (Tom), Chen, Y.D.I. (Yii-Der Ida), Psaty, B.M. (Bruce M.), Harrris, T.B. (Tamara B.), Launer, L.J. (Lenore), Padmanabhan, S. (Sandosh), Dominiczak, A. (Anna), Huang, P.L. (Paul L.), Xie, Z. (Zhijun), Ellinor, P.T. (Patrick), Kors, J.A. (Jan), Campbell, A. (Archie), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Tobin, M.D. (Martin), Bork-Jensen, J. (Jette), Hansen, T. (Torben), Pedersen, O. (Oluf), Linneberg, A. (Allan), Sinner, M.F. (Moritz), Peters, A. (Annette), Waldenberger, M. (Melanie), Meitinger, T. (Thomas), Perz, S. (Siegfried), Kolcic, I. (Ivana), Rudan, I. (Igor), Boer, R.A. (Rudolf) de, Meer, P. (Peter) van der, Lin, H.J. (Henry J.), Taylor, K.D. (Kent), Mutsert, R. (Reneé) de, Trompet, S. (Stella), Jukema, J.W. (Jan Wouter), Maan, A.C. (Arie C.), Stricker, B.H.Ch. (Bruno), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A. (André), Völker, U. (Uwe), Homuth, G. (Georg), Völzke, H. (Henry), Felix, S.B. (Stephan), Mangino, M. (Massimo), Spector, T.D. (Timothy), Bots, M.L. (Michiel), Perez, M. (Marco), Raitakari, O. (Olli), Kähönen, M. (Mika), Mononen, N. (Nina), Gudnason, V. (Vilmundur), Munroe, P. (Patricia), Lubitz, S.A. (Steven A.), Duijn, C.M. (Cornelia) van, Newton-Cheh, C. (Christopher), Hayward, C. (Caroline), Rosand, J. (Jonathan), Samani, N.J. (Nilesh J.), Kanters, J.K., Wilson, J.F. (James), Kääb, S. (Stefan), Polasek, O. (Ozren), van der Harst, P. (Pim), Heckbert, S.R. (Susan), Rotter, J.I. (Jerome I.), Mook-Kanamori, D.O. (Dennis O.), Eijgelsheim, M. (Mark), Dörr, M. (Marcus), Jamshidi, Y. (Yalda), Asselbergs, F.W. (Folkert W.), Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Arking, D.E. (Dan), Sotoodehnia, N. (Nona), Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Albert), Warren, H. (Helen), Lin, H. (Honghuang), Isaacs, A. (Aaron), Liu, C.-T. (Ching-Ti), Marten, J. (Jonathan), Radmanesh, F. (Farid), Hall, L.M. (Leanne M.), Grarup, N. (Niels), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Huffman, J.E. (Jennifer E.), Verweij, N. (Niek), Guo, X. (Xiuqing), Yao, J. (Jie), Li-Gao, R. (Ruifang), Berg, M.E. (Marten) van den, Weiss, S. (Stefan), Prins, B.P. (Bram P.), Setten, J. (Jessica) van, Haessler, J. (Jeff), Lyytikäinen, L.-P. (Leo-Pekka), Li, M. (Man), Alonso, A. (Alvaro), Soliman, E.Z. (Elsayed Z.), Bis, J.C. (Joshua), Austin, T. (Tom), Chen, Y.D.I. (Yii-Der Ida), Psaty, B.M. (Bruce M.), Harrris, T.B. (Tamara B.), Launer, L.J. (Lenore), Padmanabhan, S. (Sandosh), Dominiczak, A. (Anna), Huang, P.L. (Paul L.), Xie, Z. (Zhijun), Ellinor, P.T. (Patrick), Kors, J.A. (Jan), Campbell, A. (Archie), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Tobin, M.D. (Martin), Bork-Jensen, J. (Jette), Hansen, T. (Torben), Pedersen, O. (Oluf), Linneberg, A. (Allan), Sinner, M.F. (Moritz), Peters, A. (Annette), Waldenberger, M. (Melanie), Meitinger, T. (Thomas), Perz, S. (Siegfried), Kolcic, I. (Ivana), Rudan, I. (Igor), Boer, R.A. (Rudolf) de, Meer, P. (Peter) van der, Lin, H.J. (Henry J.), Taylor, K.D. (Kent), Mutsert, R. (Reneé) de, Trompet, S. (Stella), Jukema, J.W. (Jan Wouter), Maan, A.C. (Arie C.), Stricker, B.H.Ch. (Bruno), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A. (André), Völker, U. (Uwe), Homuth, G. (Georg), Völzke, H. (Henry), Felix, S.B. (Stephan), Mangino, M. (Massimo), Spector, T.D. (Timothy), Bots, M.L. (Michiel), Perez, M. (Marco), Raitakari, O. (Olli), Kähönen, M. (Mika), Mononen, N. (Nina), Gudnason, V. (Vilmundur), Munroe, P. (Patricia), Lubitz, S.A. (Steven A.), Duijn, C.M. (Cornelia) van, Newton-Cheh, C. (Christopher), Hayward, C. (Caroline), Rosand, J. (Jonathan), Samani, N.J. (Nilesh J.), Kanters, J.K., Wilson, J.F. (James), Kääb, S. (Stefan), Polasek, O. (Ozren), van der Harst, P. (Pim), Heckbert, S.R. (Susan), Rotter, J.I. (Jerome I.), Mook-Kanamori, D.O. (Dennis O.), Eijgelsheim, M. (Mark), Dörr, M. (Marcus), Jamshidi, Y. (Yalda), Asselbergs, F.W. (Folkert W.), Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Arking, D.E. (Dan), and Sotoodehnia, N. (Nona)
Abstract: BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
Published: 2018
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25. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author: Setten, J. (Jessica) van, Brody, J.A. (Jennifer A.), Jamshidi, Y. (Yalda), Swenson, B.R. (Brenton R.), Butler, A.M. (Anne M.), Campbell, H. (Harry), Del Greco, F.M. (Fabiola), Evans, D.S. (Daniel), Gibson, Q. (Quince), Gudbjartsson, D.F. (Daniel), Kerr, K.F. (Kathleen), Krijthe, B.P. (Bouwe), Lyytikäinen, L.-P. (Leo-Pekka), Müller, C. (Christian), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Padmanabhan, S. (Sandosh), Ritchie, M.D. (Marylyn D.), Robino, A. (Antonietta), Smith, A.V. (Albert), Steri, M. (Maristella), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), Ulivi, S. (Sheila), Verweij, N. (Niek), Yin, X. (Xiaoyan), Arnar, D.O. (David O.), Asselbergs, F.W. (Folkert W.), Bader, J.S. (Joel), Barnard, J. (John), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boerwinkle, E. (Eric), Bradford, Y. (Yuki), Buckley, B.M. (Brendan M.), Chung, M.K. (Mina), Crawford, D. (Dana), Hoed, M. (Marcel) den, Denny, J.C. (Joshua C.), Dominiczak, A. (Anna), Ehret, G.B. (Georg B.), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Felix, S.B. (Stephan), Franco, O.H. (Oscar), Franke, L. (Lude), Harris, T.B. (Tamara), Holm, H. (Hilma), Ilaria, G. (Gandin), Iorio, A. (Annamaria), Kähönen, M. (Mika), Kolcic, I. (Ivana), Kors, J.A. (Jan), Lakatta, E. (Edward), Launer, L.J. (Lenore), Lin, H. (Honghuang), Lin, H.J. (Henry J.), Loos, R.J.F. (Ruth), Lubitz, S.A. (Steven A.), MacFarlane, P.W. (Peter), Magnani, J.W. (Jared), Leach, I.M. (Irene Mateo), Meitinger, T. (Thomas), Mitchell, B.D. (Braxton), Munzel, T. (Thomas), Papanicolaou, G.J. (George J.), Peters, A. (Annette), Pfeufer, A. (Arne), Pramstaller, P.P. (Peter Paul), Raitakari, O. (Olli), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Schlessinger, D. (David), Silva Aldana, C.T. (Claudia), Sinner, M.F. (Moritz), Smith, J.D. (Jonathan), Snieder, H. (Harold), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Stott, D.J. (David. J.), Strauch, K. (Konstantin), Tarasov, K.V. (Kirill V.), Thorsteinsdottir, U. (Unnur), Uitterlinden, A.G. (André), Wagoner, D.R. (David) van, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Jan Westra, H. (Harm), Wild, P.S. (Philipp), Zeller, T. (Tanja), Alonso, A. (Alvaro), Avery, C.L., Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Cucca, F. (Francesco), Dörr, M. (Marcus), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Gudnason, V. (Vilmundur), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Hicks, A.A. (Andrew A.), Jukema, J.W. (Jan Wouter), Kääb, S. (Stefan), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Munroe, P. (Patricia), Parsa, A. (Afshin), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Roden, D.M. (Dan), Schnabel, R.B. (Renate), Sinagra, G. (Gianfranco), Zwart, J-A. (John-Anker), Stricker, B.H.Ch. (Bruno), van der Harst, P. (Pim), Duijn, C.M. (Cornelia) van, Wilson, J.F. (James F.), Gharib, S.A. (Sina), Bakker, P.I.W. (Paul) de, Isaacs, A. (Aaron), Arking, D.E. (Dan), Sotoodehnia, N. (Nona), Setten, J. (Jessica) van, Brody, J.A. (Jennifer A.), Jamshidi, Y. (Yalda), Swenson, B.R. (Brenton R.), Butler, A.M. (Anne M.), Campbell, H. (Harry), Del Greco, F.M. (Fabiola), Evans, D.S. (Daniel), Gibson, Q. (Quince), Gudbjartsson, D.F. (Daniel), Kerr, K.F. (Kathleen), Krijthe, B.P. (Bouwe), Lyytikäinen, L.-P. (Leo-Pekka), Müller, C. (Christian), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Padmanabhan, S. (Sandosh), Ritchie, M.D. (Marylyn D.), Robino, A. (Antonietta), Smith, A.V. (Albert), Steri, M. (Maristella), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), Ulivi, S. (Sheila), Verweij, N. (Niek), Yin, X. (Xiaoyan), Arnar, D.O. (David O.), Asselbergs, F.W. (Folkert W.), Bader, J.S. (Joel), Barnard, J. (John), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boerwinkle, E. (Eric), Bradford, Y. (Yuki), Buckley, B.M. (Brendan M.), Chung, M.K. (Mina), Crawford, D. (Dana), Hoed, M. (Marcel) den, Denny, J.C. (Joshua C.), Dominiczak, A. (Anna), Ehret, G.B. (Georg B.), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Felix, S.B. (Stephan), Franco, O.H. (Oscar), Franke, L. (Lude), Harris, T.B. (Tamara), Holm, H. (Hilma), Ilaria, G. (Gandin), Iorio, A. (Annamaria), Kähönen, M. (Mika), Kolcic, I. (Ivana), Kors, J.A. (Jan), Lakatta, E. (Edward), Launer, L.J. (Lenore), Lin, H. (Honghuang), Lin, H.J. (Henry J.), Loos, R.J.F. (Ruth), Lubitz, S.A. (Steven A.), MacFarlane, P.W. (Peter), Magnani, J.W. (Jared), Leach, I.M. (Irene Mateo), Meitinger, T. (Thomas), Mitchell, B.D. (Braxton), Munzel, T. (Thomas), Papanicolaou, G.J. (George J.), Peters, A. (Annette), Pfeufer, A. (Arne), Pramstaller, P.P. (Peter Paul), Raitakari, O. (Olli), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Schlessinger, D. (David), Silva Aldana, C.T. (Claudia), Sinner, M.F. (Moritz), Smith, J.D. (Jonathan), Snieder, H. (Harold), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Stott, D.J. (David. J.), Strauch, K. (Konstantin), Tarasov, K.V. (Kirill V.), Thorsteinsdottir, U. (Unnur), Uitterlinden, A.G. (André), Wagoner, D.R. (David) van, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Jan Westra, H. (Harm), Wild, P.S. (Philipp), Zeller, T. (Tanja), Alonso, A. (Alvaro), Avery, C.L., Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Cucca, F. (Francesco), Dörr, M. (Marcus), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Gudnason, V. (Vilmundur), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Hicks, A.A. (Andrew A.), Jukema, J.W. (Jan Wouter), Kääb, S. (Stefan), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Munroe, P. (Patricia), Parsa, A. (Afshin), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Roden, D.M. (Dan), Schnabel, R.B. (Renate), Sinagra, G. (Gianfranco), Zwart, J-A. (John-Anker), Stricker, B.H.Ch. (Bruno), van der Harst, P. (Pim), Duijn, C.M. (Cornelia) van, Wilson, J.F. (James F.), Gharib, S.A. (Sina), Bakker, P.I.W. (Paul) de, Isaacs, A. (Aaron), Arking, D.E. (Dan), and Sotoodehnia, N. (Nona)
Abstract: Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
Published: 2018
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26. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author: Prins, B.P. (Bram P.), Mead, T.J. (Timothy J.), Brody, J.A. (Jennifer A.), Sveinbjornsson, G. (Gardar), Ntalla, I. (Ioanna), Bihlmeyer, N.A. (Nathan A.), Berg, M.E. (Marten) van den, Bork-Jensen, J. (Jette), Cappellani, S. (Stefania), Van Duijvenboden, S. (Stefan), Klena, N.T. (Nikolai T.), Gabriel, G.C. (George C.), Liu, X. (Xiaoqin), Gulec, C. (Cagri), Grarup, N. (Niels), Haessler, J. (Jeff), Hall, L.M. (Leanne M.), Iorio, A. (Annamaria), Isaacs, A. (Aaron), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Liu, C.-T. (Ching-Ti), Lyytikäinen, L.-P. (Leo-Pekka), Marten, J. (Jonathan), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Orini, M. (Michele), Padmanabhan, S. (Sandosh), Radmanesh, F. (Farid), Ramirez, J. (Julia), Robino, A. (Antonietta), Schwartz, M. (Molly), Setten, J. (Jessica) van, Smith, A.V. (Albert), Verweij, N. (Niek), Warren, H. (Helen), Weiss, S. (Stefan), Alonso, A. (Alvaro), Arnar, D.O. (David O.), Bots, M.L. (Michiel), Boer, R.A. (Rudolf) de, Dominiczak, A. (Anna), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Guo, X. (Xiuqing), Felix, S.B. (Stephan), Harris, T.B. (Tamara), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kors, J.A. (Jan), Lambiase, P.D. (Pier), Launer, L.J. (Lenore), Li, M. (Man), Linneberg, A. (Allan), Nelson, C.P. (Christopher P.), Pedersen, O. (Oluf), Perez, M. (Marco), Peters, A. (Annette), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Raitakari, O. (Olli), Rice, K.M. (Kenneth), Rotter, J.I. (Jerome I.), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Strauch, K. (Konstantin), Thorsteinsdottir, U. (Unnur), Tinker, A. (Andrew), Trompet, S. (Stella), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Meer, P. (Peter) van der, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Wilson, J.F. (James), Xie, Z. (Zhijun), Asselbergs, F.W. (Folkert W.), Dörr, M. (Marcus), Duijn, C.M. (Cornelia) van, Gasparini, P. (Paolo), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hansen, T. (Torben), Kääb, S. (Stefan), Kanters, J.K., Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Lin, H.J. (Henry J.), Lubitz, S.A. (Steven A.), Mook-Kanamori, D.O. (Dennis O.), Conti, F.J. (Francesco J.), Newton-Cheh, C. (Christopher), Rosand, J. (Jonathan), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Sinagra, G. (Gianfranco), Smith, B.H. (Blair), Holm, H. (Hilma), Stricker, B.H.Ch. (Bruno), Ulivi, S. (Sheila), Sotoodehnia, N. (Nona), Apte, S.S. (Suneel S.), van der Harst, P. (Pim), Zwart, J-A. (John-Anker), Munroe, P. (Patricia), Arking, D.E. (Dan), Lo, C.W. (Cecilia W.), Jamshidi, Y. (Yalda), Prins, B.P. (Bram P.), Mead, T.J. (Timothy J.), Brody, J.A. (Jennifer A.), Sveinbjornsson, G. (Gardar), Ntalla, I. (Ioanna), Bihlmeyer, N.A. (Nathan A.), Berg, M.E. (Marten) van den, Bork-Jensen, J. (Jette), Cappellani, S. (Stefania), Van Duijvenboden, S. (Stefan), Klena, N.T. (Nikolai T.), Gabriel, G.C. (George C.), Liu, X. (Xiaoqin), Gulec, C. (Cagri), Grarup, N. (Niels), Haessler, J. (Jeff), Hall, L.M. (Leanne M.), Iorio, A. (Annamaria), Isaacs, A. (Aaron), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Liu, C.-T. (Ching-Ti), Lyytikäinen, L.-P. (Leo-Pekka), Marten, J. (Jonathan), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Orini, M. (Michele), Padmanabhan, S. (Sandosh), Radmanesh, F. (Farid), Ramirez, J. (Julia), Robino, A. (Antonietta), Schwartz, M. (Molly), Setten, J. (Jessica) van, Smith, A.V. (Albert), Verweij, N. (Niek), Warren, H. (Helen), Weiss, S. (Stefan), Alonso, A. (Alvaro), Arnar, D.O. (David O.), Bots, M.L. (Michiel), Boer, R.A. (Rudolf) de, Dominiczak, A. (Anna), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Guo, X. (Xiuqing), Felix, S.B. (Stephan), Harris, T.B. (Tamara), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kors, J.A. (Jan), Lambiase, P.D. (Pier), Launer, L.J. (Lenore), Li, M. (Man), Linneberg, A. (Allan), Nelson, C.P. (Christopher P.), Pedersen, O. (Oluf), Perez, M. (Marco), Peters, A. (Annette), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Raitakari, O. (Olli), Rice, K.M. (Kenneth), Rotter, J.I. (Jerome I.), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Strauch, K. (Konstantin), Thorsteinsdottir, U. (Unnur), Tinker, A. (Andrew), Trompet, S. (Stella), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Meer, P. (Peter) van der, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Wilson, J.F. (James), Xie, Z. (Zhijun), Asselbergs, F.W. (Folkert W.), Dörr, M. (Marcus), Duijn, C.M. (Cornelia) van, Gasparini, P. (Paolo), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hansen, T. (Torben), Kääb, S. (Stefan), Kanters, J.K., Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Lin, H.J. (Henry J.), Lubitz, S.A. (Steven A.), Mook-Kanamori, D.O. (Dennis O.), Conti, F.J. (Francesco J.), Newton-Cheh, C. (Christopher), Rosand, J. (Jonathan), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Sinagra, G. (Gianfranco), Smith, B.H. (Blair), Holm, H. (Hilma), Stricker, B.H.Ch. (Bruno), Ulivi, S. (Sheila), Sotoodehnia, N. (Nona), Apte, S.S. (Suneel S.), van der Harst, P. (Pim), Zwart, J-A. (John-Anker), Munroe, P. (Patricia), Arking, D.E. (Dan), Lo, C.W. (Cecilia W.), and Jamshidi, Y. (Yalda)
Abstract: Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Published: 2018
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27. Rare and low-frequency coding variants alter human adult height

Author: Marouli, E. (Eirini), Graff, M.J. (Maud J.L.), Medina-Gomez, C. (Carolina), Lo, K.S., Wood, A.R. (Andrew), Kjaer, T.R. (Troels R.), Fine, R.S. (Rebecca S.), Lu, Y. (Yingchang), Schurmann, C. (Claudia), Highland, H. (Heather), Rüeger, S. (Sina), Thorleifsson, G. (Gudmar), Justice, A.E. (Anne), Lamparter, D. (David), Stirrups, K. (Kathy), Turcot, V. (Valérie), Young, K.L. (Kristin L.), Winkler, T.W. (Thomas W.), Esko, T. (Tõnu), Karaderi, T. (Tugce), Locke, A. (Adam), Masca, N.G.D. (Nicholas G.D.), Ng, M.C.Y. (Maggie C.Y.), Mudgal, P. (Poorva), Rivas, M.A. (Manuel), Vedantam, S. (Sailaja), Mahajan, A. (Anubha), Guo, X. (Xiuqing), Abecasis, G.R. (Gonçalo), Aben, K.K.H. (Katja), Adair, L.S. (Linda), Alam, D.S. (Dewan S.), Albrecht, E. (Eva), Allin, K.H. (Kristine H), Allison, M.A. (Matthew), Amouyel, P. (Philippe), Appel, E.V. (Emil V.), Arveiler, D. (Dominique), Asselbergs, F.W. (Folkert), Auer, P. (Paul), Balkau, B. (Beverley), Banas, B. (Bernhard), Bang, L.E. (Lia E.), Benn, M. (Marianne), Bergmann, S. (Sven), Bielak, L.F. (Lawrence F.), Blüher, M. (Matthias), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Böger, C.A. (Carsten), Bonnycastle, L.L. (Lori), Bork-Jensen, J. (Jette), Bots, M.L. (Michiel), Bottinger, E.P. (Erwin), Bowden, D.W. (Donald), Brandslund, I. (Ivan), Breen, G. (Gerome), Brilliant, M.H. (Murray H.), Broer, L. (Linda), Burt, A.D. (Alastair), Butterworth, A.S. (Adam), Carey, D.J. (David J.), Caulfield, M. (Mark), Chambers, J.C. (John), Chasman, D.I. (Daniel), Chen, Y.-D.I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Christensen, C. (Cramer), Chu, A.Y. (Audrey), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Cook, J.P. (James P.), Corley, J. (Janie), Galbany, J.C. (Jordi Corominas), Cox, A.J. (Amanda J.), Cuellar-Partida, G. (Gabriel), Danesh, J. (John), Davies, G. (Gail), Bakker, P.I.W. (Paul) de, Borst, G.J. (Gert) de, De Denus, S. (Simon), De Groot, M.C.H. (Mark C.H.), Mutsert, R. (Reneé) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Demerath, E.W. (Ellen), Hollander, A.I. (Anneke), Dennis, J. (Joe), Angelantonio, E. (Emanuele) di, Drenos, F. (Fotios), Du, M. (Mengmeng), Dunning, A.M. (Alison M.), Easton, D.F. (Douglas), Ebeling, T. (Tapani), Edwards, T.L. (Todd L.), Ellinor, P.T. (Patrick), Elliott, P. (Paul), Evangelou, E. (Evangelos), Farmaki, A.-E. (Aliki-Eleni), Faul, J.D. (Jessica D.), Feitosa, M.F. (Mary Furlan), Feng, S. (Shuang), Ferrannini, E. (Ele), Ferrario, M.M. (Marco M.), Ferrieres, J. (Jean), Florez, J.C. (Jose), Ford, I., Fornage, M. (Myriam), Franks, P.W. (Paul), Frikke-Schmidt, R. (Ruth), Galesloot, T.E. (Tessel), Gan, W. (Wei), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Giri, A. (Ayush), Girotto, S., Gordon, S.D. (Scott D.), Gordon-Larsen, P. (Penny), Gorski, M. (Mathias), Grarup, N. (Niels), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Gustafsson, S. (Stefan), Hansen, T. (T.), Harris, K.M. (Kathleen Mullan), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), He, L. (Liang), Heid, I.M. (Iris), Heikkilä, K. (Kauko), Helgeland, Ø. (Øyvind), Hernesniemi, J. (Jussi), Hewit, A.W. (Alex), Hocking, L.J. (Lynne), Hollensted, M. (Mette), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Howson, J.M.M. (Joanna M.M.), Hoyng, C.B. (Carel), Huang, P.L. (Paul L.), Hveem, K. (Kristian), Ikram, M.K. (Kamran), Ingelsson, E. (Erik), Jackson, A.U. (Anne), Jansson, J.-H. (Jan-Håkan), Jarvik, G.P. (Gail), Jensen, G.B. (Gorm B.), Jhun, M.A. (Min A.), Jia, Y. (Yucheng), Jiang, X. (Xuejuan), Johansson, S. (Stefan), Jørgensen, M.E. (Marit E.), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kahali, B. (Bratati), Kahn, R. (René), Kähönen, M. (Mika), Kamstrup, P.R. (Pia R.), Kanoni, S. (Stavroula), Kaprio, J. (Jaakko), Karaleftheri, M. (Maria), Kardia, S.L.R. (Sharon L.R.), Karpe, F. (Fredrik), Kee, F. (Frank), Keeman, J.N., Kiemeney, L.A.L.M. (Bart), Kitajima, H. (Hidetoshi), Kluivers, K.B. (Kirsten B.), Kocher, T., Komulainen, P. (Pirjo), Kontto, J. (Jukka), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Kovacs, P. (Peter), Kriebel, J. (Jennifer), Kuivaniemi, H. (Helena), Küry, S. (Sébastien), Kuusisto, J. (Johanna), La Bianca, M. (Martina), Laakso, M. (Markku), Lakka, T.A. (Timo), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Larson, E.B. (Eric B.), Lee, I.-T. (I-Te), Lehtimäki, T. (Terho), Lewis, C.E. (Cora E.), Li, H. (Huaixing), Li, J. (Jin), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Lin, L.-A. (Li-An), Lin, X. (Xu), Kao, W.H.L. (Wen), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y. (Yeheng), Liu, Y. (YongMei), Lophatananon, A. (Artitaya), Luan, J. (Jian'An), Lubitz, S.A. (Steven), Lyytikäinen, L.-P. (Leo-Pekka), Mackey, D.A. (David A.), Madden, P.A. (Pamela), Manning, A.K. (Alisa), Männistö, S. (Satu), Marenne, G. (Gaëlle), Marten, J. (Jonathan), Martin, N.G. (Nicholas), Mazul, A.L. (Angela L.), Meidtner, K. (Karina), Metspalu, A. (Andres), Mitchell, P. (Paul), Mohlke, K.L. (Karen), Mook-Kanamori, D.O. (Dennis), Morgan, A. (Anna), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Neville, M.J. (Matthew), Nielsen, S.F. (Sune), Nikus, K. (Kjell), Njolstad, P. (Pal), Nordestgaard, B.G. (Børge), Ntalla, I. (Ioanna), O'Connel, J.R. (Jeffrey R.), Oksa, H. (Heikki), Loohuis, L.M.O. (Loes M. Olde), Ophoff, R.A. (Roel), Owen, K.R. (Katharine R.), Packard, C.J. (Chris J.), Padmanabhan, S. (Sandosh), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Patel, A.P. (Aniruddh), Pattie, A. (Alison), Pedersen, O. (Oluf), Peissig, P.L. (Peggy L.), Peloso, G.M. (Gina), Pennell, C.E. (Craig), Perola, M. (Markus), Perry, J.A. (James A.), Perry, J.R.B. (John R.B.), Person, A.D. (Anthony), Pirie, A. (Ailith), Polasek, O. (Ozren), Posthuma, D. (Danielle), Raitakari, O.T. (Olli T.), Rasheed, A. (Asif), Rauramaa, R. (Rainer), Reilly, D.F. (Dermot F.), Reiner, A. (Alexander), Renström, F. (Frida), Ridker, P.M. (Paul), Rioux, J.D. (John), Robertson, N.R. (Neil), Robino, A. (Antonietta), Rolandsson, O. (Olov), Rudan, I. (Igor), Ruth, K.S. (Katherine S.), Saleheen, D. (Danish), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Sandow, K. (Kevin), Sapkota, Y. (Yadav), Sattar, N. (Naveed), Schmidt, M.K. (Marjanka), Schreiner, P.J. (Pamela), Schulze, M.B. (Matthias B), Scott, R.A. (Robert), Segura-Lepe, M.P. (Marcelo P.), Shah, S.H. (Svati), Sim, X. (Xueling), Sivapalaratnam, S. (Suthesh), Small, K.S. (Kerrin), Smith, A.V. (Albert Vernon), Smith, J.A. (Jennifer A), Southam, L. (Lorraine), Spector, T.D. (Timothy), Speliotes, E.K. (Elizabeth K.), Starr, J.M. (John), Steinthorsdottir, V. (Valgerdur), Stringham, H.M. (Heather), Stumvoll, M. (Michael), Surendran, P. (Praveen), Hart't, L.M. (Leen M.), Tansey, K.E. (Katherine E.), Tardif, J.-C. (Jean-Claude), Taylor, K.D. (Kent), Teumer, A. (Alexander), Thompson, D. (Deborah), Thorsteinsdottir, U. (Unnur), Thuesen, B.H. (Betina H.), Tönjes, A. (Anke), Tromp, G. (Gerard), Trompet, S. (Stella), Tsafantakis, E. (Emmanouil), Tuomilehto, J. (Jaakko), Tybjaerg-Hansen, A. (Anne), Tyrer, J.P. (Jonathan), Uher, R., Uitterlinden, A.G. (André), Ulivi, S. (Sheila), Van Der Laan, S.W. (Sander W.), Van Der Leij, A.R. (Andries R.), Duijn, C.M. (Cornelia) van, Schoor, N.M. (Natasja) van, Setten, J. (Jessica) van, Varbo, A. (Anette), Varga, T.V. (Tibor V.), Varma, R. (Rohit), Velez Edwards, D.R. (Digna R.), Vermeulen, S.H.H.M. (Sita), Vestergaard, H. (Henrik), Vitart, V. (Veronique), Vogt, T.F. (Thomas F.), Vozzi, D. (Diego), Walker, M. (Mark), Wang, F. (Feijie), Wang, C.A. (Carol A.), Wang, S. (Shuai), Wang, Y. (Yiqin), Wareham, N.J. (Nicholas J.), Warren, H. (Helen), Wessel, J. (Jennifer), Willems, S.M. (Sara), Wilson, J.F. (James), Witte, D.R. (Deniel), Woods, M.O. (Michael), Wu, Y. (Ying), Yaghootkar, H. (Hanieh), Yao, J. (Jiefen), Yao, P. (Pang), Yerges-Armstrong, L.M. (Laura), Young, R. (Robin), Zeggini, E. (Eleftheria), Zhan, X. (Xiaowei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zhao, W. (Wei), Zheng, H. (He), Zhou, W. (Wei), Rotter, J.I. (Jerome I.), Boehnke, M. (Michael), Kathiresan, S. (Sekar), McCarthy, M.I. (Mark I.), Willer, C.J. (Cristen), Zwart, J-A. (John-Anker), Borecki, I.B. (Ingrid), Liu, D. (Dajiang), North, K.E. (Kari), Heard-Costa, N.L. (Nancy), Pers, T.H. (Tune), Lindgren, C.M. (Cecilia M.), Oxvig, C. (Claus), Kutalik, Z. (Zoltán), Rivadeneira Ramirez, F. (Fernando), Loos, R.J.F. (Ruth), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Deloukas, P. (Panos), Lettre, G. (Guillaume), Marouli, E. (Eirini), Graff, M.J. (Maud J.L.), Medina-Gomez, C. (Carolina), Lo, K.S., Wood, A.R. (Andrew), Kjaer, T.R. (Troels R.), Fine, R.S. (Rebecca S.), Lu, Y. (Yingchang), Schurmann, C. (Claudia), Highland, H. (Heather), Rüeger, S. (Sina), Thorleifsson, G. (Gudmar), Justice, A.E. (Anne), Lamparter, D. (David), Stirrups, K. (Kathy), Turcot, V. (Valérie), Young, K.L. (Kristin L.), Winkler, T.W. (Thomas W.), Esko, T. (Tõnu), Karaderi, T. (Tugce), Locke, A. (Adam), Masca, N.G.D. (Nicholas G.D.), Ng, M.C.Y. (Maggie C.Y.), Mudgal, P. (Poorva), Rivas, M.A. (Manuel), Vedantam, S. (Sailaja), Mahajan, A. (Anubha), Guo, X. (Xiuqing), Abecasis, G.R. (Gonçalo), Aben, K.K.H. (Katja), Adair, L.S. (Linda), Alam, D.S. (Dewan S.), Albrecht, E. (Eva), Allin, K.H. (Kristine H), Allison, M.A. (Matthew), Amouyel, P. (Philippe), Appel, E.V. (Emil V.), Arveiler, D. (Dominique), Asselbergs, F.W. (Folkert), Auer, P. (Paul), Balkau, B. (Beverley), Banas, B. (Bernhard), Bang, L.E. (Lia E.), Benn, M. (Marianne), Bergmann, S. (Sven), Bielak, L.F. (Lawrence F.), Blüher, M. (Matthias), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Böger, C.A. (Carsten), Bonnycastle, L.L. (Lori), Bork-Jensen, J. (Jette), Bots, M.L. (Michiel), Bottinger, E.P. (Erwin), Bowden, D.W. (Donald), Brandslund, I. (Ivan), Breen, G. (Gerome), Brilliant, M.H. (Murray H.), Broer, L. (Linda), Burt, A.D. (Alastair), Butterworth, A.S. (Adam), Carey, D.J. (David J.), Caulfield, M. (Mark), Chambers, J.C. (John), Chasman, D.I. (Daniel), Chen, Y.-D.I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Christensen, C. (Cramer), Chu, A.Y. (Audrey), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Cook, J.P. (James P.), Corley, J. (Janie), Galbany, J.C. (Jordi Corominas), Cox, A.J. (Amanda J.), Cuellar-Partida, G. (Gabriel), Danesh, J. (John), Davies, G. (Gail), Bakker, P.I.W. (Paul) de, Borst, G.J. (Gert) de, De Denus, S. (Simon), De Groot, M.C.H. (Mark C.H.), Mutsert, R. (Reneé) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Demerath, E.W. (Ellen), Hollander, A.I. (Anneke), Dennis, J. (Joe), Angelantonio, E. (Emanuele) di, Drenos, F. (Fotios), Du, M. (Mengmeng), Dunning, A.M. (Alison M.), Easton, D.F. (Douglas), Ebeling, T. (Tapani), Edwards, T.L. (Todd L.), Ellinor, P.T. (Patrick), Elliott, P. (Paul), Evangelou, E. (Evangelos), Farmaki, A.-E. (Aliki-Eleni), Faul, J.D. (Jessica D.), Feitosa, M.F. (Mary Furlan), Feng, S. (Shuang), Ferrannini, E. (Ele), Ferrario, M.M. (Marco M.), Ferrieres, J. (Jean), Florez, J.C. (Jose), Ford, I., Fornage, M. (Myriam), Franks, P.W. (Paul), Frikke-Schmidt, R. (Ruth), Galesloot, T.E. (Tessel), Gan, W. (Wei), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Giri, A. (Ayush), Girotto, S., Gordon, S.D. (Scott D.), Gordon-Larsen, P. (Penny), Gorski, M. (Mathias), Grarup, N. (Niels), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Gustafsson, S. (Stefan), Hansen, T. (T.), Harris, K.M. (Kathleen Mullan), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), He, L. (Liang), Heid, I.M. (Iris), Heikkilä, K. (Kauko), Helgeland, Ø. (Øyvind), Hernesniemi, J. (Jussi), Hewit, A.W. (Alex), Hocking, L.J. (Lynne), Hollensted, M. (Mette), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Howson, J.M.M. (Joanna M.M.), Hoyng, C.B. (Carel), Huang, P.L. (Paul L.), Hveem, K. (Kristian), Ikram, M.K. (Kamran), Ingelsson, E. (Erik), Jackson, A.U. (Anne), Jansson, J.-H. (Jan-Håkan), Jarvik, G.P. (Gail), Jensen, G.B. (Gorm B.), Jhun, M.A. (Min A.), Jia, Y. (Yucheng), Jiang, X. (Xuejuan), Johansson, S. (Stefan), Jørgensen, M.E. (Marit E.), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kahali, B. (Bratati), Kahn, R. (René), Kähönen, M. (Mika), Kamstrup, P.R. (Pia R.), Kanoni, S. (Stavroula), Kaprio, J. (Jaakko), Karaleftheri, M. (Maria), Kardia, S.L.R. (Sharon L.R.), Karpe, F. (Fredrik), Kee, F. (Frank), Keeman, J.N., Kiemeney, L.A.L.M. (Bart), Kitajima, H. (Hidetoshi), Kluivers, K.B. (Kirsten B.), Kocher, T., Komulainen, P. (Pirjo), Kontto, J. (Jukka), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Kovacs, P. (Peter), Kriebel, J. (Jennifer), Kuivaniemi, H. (Helena), Küry, S. (Sébastien), Kuusisto, J. (Johanna), La Bianca, M. (Martina), Laakso, M. (Markku), Lakka, T.A. (Timo), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Larson, E.B. (Eric B.), Lee, I.-T. (I-Te), Lehtimäki, T. (Terho), Lewis, C.E. (Cora E.), Li, H. (Huaixing), Li, J. (Jin), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Lin, L.-A. (Li-An), Lin, X. (Xu), Kao, W.H.L. (Wen), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y. (Yeheng), Liu, Y. (YongMei), Lophatananon, A. (Artitaya), Luan, J. (Jian'An), Lubitz, S.A. (Steven), Lyytikäinen, L.-P. (Leo-Pekka), Mackey, D.A. (David A.), Madden, P.A. (Pamela), Manning, A.K. (Alisa), Männistö, S. (Satu), Marenne, G. (Gaëlle), Marten, J. (Jonathan), Martin, N.G. (Nicholas), Mazul, A.L. (Angela L.), Meidtner, K. (Karina), Metspalu, A. (Andres), Mitchell, P. (Paul), Mohlke, K.L. (Karen), Mook-Kanamori, D.O. (Dennis), Morgan, A. (Anna), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Neville, M.J. (Matthew), Nielsen, S.F. (Sune), Nikus, K. (Kjell), Njolstad, P. (Pal), Nordestgaard, B.G. (Børge), Ntalla, I. (Ioanna), O'Connel, J.R. (Jeffrey R.), Oksa, H. (Heikki), Loohuis, L.M.O. (Loes M. Olde), Ophoff, R.A. (Roel), Owen, K.R. (Katharine R.), Packard, C.J. (Chris J.), Padmanabhan, S. (Sandosh), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Patel, A.P. (Aniruddh), Pattie, A. (Alison), Pedersen, O. (Oluf), Peissig, P.L. (Peggy L.), Peloso, G.M. (Gina), Pennell, C.E. (Craig), Perola, M. (Markus), Perry, J.A. (James A.), Perry, J.R.B. (John R.B.), Person, A.D. (Anthony), Pirie, A. (Ailith), Polasek, O. (Ozren), Posthuma, D. (Danielle), Raitakari, O.T. (Olli T.), Rasheed, A. (Asif), Rauramaa, R. (Rainer), Reilly, D.F. (Dermot F.), Reiner, A. (Alexander), Renström, F. (Frida), Ridker, P.M. (Paul), Rioux, J.D. (John), Robertson, N.R. (Neil), Robino, A. (Antonietta), Rolandsson, O. (Olov), Rudan, I. (Igor), Ruth, K.S. (Katherine S.), Saleheen, D. (Danish), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Sandow, K. (Kevin), Sapkota, Y. (Yadav), Sattar, N. (Naveed), Schmidt, M.K. (Marjanka), Schreiner, P.J. (Pamela), Schulze, M.B. (Matthias B), Scott, R.A. (Robert), Segura-Lepe, M.P. (Marcelo P.), Shah, S.H. (Svati), Sim, X. (Xueling), Sivapalaratnam, S. (Suthesh), Small, K.S. (Kerrin), Smith, A.V. (Albert Vernon), Smith, J.A. (Jennifer A), Southam, L. (Lorraine), Spector, T.D. (Timothy), Speliotes, E.K. (Elizabeth K.), Starr, J.M. (John), Steinthorsdottir, V. (Valgerdur), Stringham, H.M. (Heather), Stumvoll, M. (Michael), Surendran, P. (Praveen), Hart't, L.M. (Leen M.), Tansey, K.E. (Katherine E.), Tardif, J.-C. (Jean-Claude), Taylor, K.D. (Kent), Teumer, A. (Alexander), Thompson, D. (Deborah), Thorsteinsdottir, U. (Unnur), Thuesen, B.H. (Betina H.), Tönjes, A. (Anke), Tromp, G. (Gerard), Trompet, S. (Stella), Tsafantakis, E. (Emmanouil), Tuomilehto, J. (Jaakko), Tybjaerg-Hansen, A. (Anne), Tyrer, J.P. (Jonathan), Uher, R., Uitterlinden, A.G. (André), Ulivi, S. (Sheila), Van Der Laan, S.W. (Sander W.), Van Der Leij, A.R. (Andries R.), Duijn, C.M. (Cornelia) van, Schoor, N.M. (Natasja) van, Setten, J. (Jessica) van, Varbo, A. (Anette), Varga, T.V. (Tibor V.), Varma, R. (Rohit), Velez Edwards, D.R. (Digna R.), Vermeulen, S.H.H.M. (Sita), Vestergaard, H. (Henrik), Vitart, V. (Veronique), Vogt, T.F. (Thomas F.), Vozzi, D. (Diego), Walker, M. (Mark), Wang, F. (Feijie), Wang, C.A. (Carol A.), Wang, S. (Shuai), Wang, Y. (Yiqin), Wareham, N.J. (Nicholas J.), Warren, H. (Helen), Wessel, J. (Jennifer), Willems, S.M. (Sara), Wilson, J.F. (James), Witte, D.R. (Deniel), Woods, M.O. (Michael), Wu, Y. (Ying), Yaghootkar, H. (Hanieh), Yao, J. (Jiefen), Yao, P. (Pang), Yerges-Armstrong, L.M. (Laura), Young, R. (Robin), Zeggini, E. (Eleftheria), Zhan, X. (Xiaowei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zhao, W. (Wei), Zheng, H. (He), Zhou, W. (Wei), Rotter, J.I. (Jerome I.), Boehnke, M. (Michael), Kathiresan, S. (Sekar), McCarthy, M.I. (Mark I.), Willer, C.J. (Cristen), Zwart, J-A. (John-Anker), Borecki, I.B. (Ingrid), Liu, D. (Dajiang), North, K.E. (Kari), Heard-Costa, N.L. (Nancy), Pers, T.H. (Tune), Lindgren, C.M. (Cecilia M.), Oxvig, C. (Claus), Kutalik, Z. (Zoltán), Rivadeneira Ramirez, F. (Fernando), Loos, R.J.F. (Ruth), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Deloukas, P. (Panos), and Lettre, G. (Guillaume)
Abstract: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of I
Published: 2017
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28. Prognostic value of serial galectin-3 measurements in patients with acute heart failure

Author: Vark, L.C. (Laura) van, Lesman-Leegte, I. (Ivonne), Baart, S.J. (Sara), Postmus, D. (Douwe), Pinto, Y.M. (Yigal), Boer, R.A. (Rudolf) de, Asselbergs, F.W. (Folkert W.), Wajon, E.M.C.J. (Elly), Orsel, J.G. (Joke G.), Boersma, H. (Eric), Hillege, H.L. (Hans), Martijn Akkerhuis, K. (K.), Nagelsmit, M.J. (Michiel J.), Brunner La Rocca, H.P. (Hans Peter), Linssen, G.C.M. (Gerard), Terpstra, W.F. (Willem F.), Akkerhuis, K.M. (K. Martijn), Liem, A.H. (Anho H.), Wardeh, A.J. (Alexander), Miltenburg, A. (Addy) van, Bos, E.J. (Ewout) van den, de Ridder, S.P.J. (Stijn P.J.), Vark, L.C. (Laura) van, Lesman-Leegte, I. (Ivonne), Baart, S.J. (Sara), Postmus, D. (Douwe), Pinto, Y.M. (Yigal), Boer, R.A. (Rudolf) de, Asselbergs, F.W. (Folkert W.), Wajon, E.M.C.J. (Elly), Orsel, J.G. (Joke G.), Boersma, H. (Eric), Hillege, H.L. (Hans), Martijn Akkerhuis, K. (K.), Nagelsmit, M.J. (Michiel J.), Brunner La Rocca, H.P. (Hans Peter), Linssen, G.C.M. (Gerard), Terpstra, W.F. (Willem F.), Akkerhuis, K.M. (K. Martijn), Liem, A.H. (Anho H.), Wardeh, A.J. (Alexander), Miltenburg, A. (Addy) van, Bos, E.J. (Ewout) van den, and de Ridder, S.P.J. (Stijn P.J.)
Abstract: Background--Several clinical studies have evaluated the association between galectin-3 levels and outcome in patients with heart failure (HF). However, little is known about the predictive value of repeated galectin-3 measurements. This study evaluates the prognostic value of repeated time-dependent galectin-3 measurements in acute HF patients. Methods and Results--In the TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients with Heart Failure) clinical cohort study, 496 acute HF patients were enrolled in 14 hospitals in The Netherlands, between 2009 and 2014. Repeated blood samples (7) were drawn during 1-year follow-up. Associations between repeated biomarker measurements and the primary end point were assessed using a joint model. Median age was 74 years and 37% were women. The primary end point, composite of all-cause mortality and HF rehospitalization, was reached in 188 patients (40%), during a median follow-up of 325 days (interquartile range 85-401). The median baseline galectin-3 level was 24 ng/mL (interquartile range 18-34). The mean number of galectin-3 measurements available per patient was 4.3. When repeated measurements were taken into account, the adjusted hazard ratio per 1 SD increase of the galectin-3 level (on the log2 scale) at any time point increased to 1.67 (95% confidence interval, 1.24-2.23, P < 0.001). After additional adjustment for repeated N-terminal pro-brain natriuretic peptide measurements, the association remained statistically significant. Conclusions--Repeated galectin-3 measurements appeared to be a strong predictor of outcome in acute HF patients, independent of N-terminal pro-brain natriuretic peptide. Hence, galectin-3 may be helpful in clinical practice for prognostication and treatment monitoring.
Published: 2017
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29. Gene Set Enrichment Analyses: Lessons learned from the heart failure phenotype

Author: Tragante, V. (Vinicius), Gho, J.M.I.H. (Johannes), Felix, J.F. (Janine), Vasan, R.S. (Ramachandran S.), Smith, N.L. (Nicholas), Voight, B.F. (Benjamin), Palmer, C.N.A. (Colin), Harst, P. (Pim) van der, Moore, J.H. (Jason), Asselbergs, F.W. (Folkert), Tragante, V. (Vinicius), Gho, J.M.I.H. (Johannes), Felix, J.F. (Janine), Vasan, R.S. (Ramachandran S.), Smith, N.L. (Nicholas), Voight, B.F. (Benjamin), Palmer, C.N.A. (Colin), Harst, P. (Pim) van der, Moore, J.H. (Jason), and Asselbergs, F.W. (Folkert)
Abstract: Background: Genetic studies for complex diseases have predominantly discovered main effects at individual loci, but have not focused on genomic and environmental contexts important for a phenotype. Gene Set Enrichment Analysis (GSEA) aims to address this by identifying sets of genes or biological pathways contributing to a phenotype, through gene-gene interactions or other mechanisms, which are not the focus of conventional association methods. Results: Approaches that utilize GSEA can now take input from array chips, either gene-centric or genome-wide, but are highly sensitive to study design, SNP selection and pruning strategies, SNP-to-gene mapping, and pathway definitions. Here, we present lessons learned from our experience with GSEA of heart failure, a particularly challenging phenotype due to its underlying heterogeneous etiology. Conclusions: This case study shows that proper data handling is essential to avoid false-positive results. Well-defined pipelines for quality control are needed to avoid reporting spurious results using GSEA.
Published: 2017
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30. Discovery of novel heart rate-associated loci using the Exome Chip

Author: Berg, M.E. (Marten) van den, Warren, H. (Helen), Cabrera, C.P. (Claudia P.), Verweij, N. (Niek), Mifsud, B. (Borbala), Haessler, J. (Jeff), Bihlmeyer, N.A. (Nathan A.), Fu, Y.-P. (Yi-Ping), Weiss, S. (Stefan), Lin, H.J. (Henry J.), Grarup, N. (Niels), Li-Gao, R. (Ruifang), Pistis, G. (Giorgio), Shah, N. (Nisha), Brody, J.A. (Jennifer A.), Müller-Nurasyid, M. (Martina), Lin, H. (Honghuang), Mei, H. (Hao), Smith, A.V. (Albert V.), Lyytikäinen, L.-P. (Leo-Pekka), Hall, L.M. (Leanne M.), Setten, J. (Jessica) van, Trompet, S. (Stella), Prins, B.P. (Bram P.), Isaacs, A.J. (Aaron), Radmanesh, F. (Farid), Marten, J. (Jonathan), Entwistle, A. (Aiman), Kors, J.A. (Jan), Silva Aldana, C.T. (Claudia), Alonso, A. (Alvaro), Bis, J.C. (Joshua), Boer, R.A. (Rudolf) de, Haan, H.G. (Hugoline) de, Mutsert, R. (Reneé) de, Dedoussis, G.V. (George), Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Ellinor, P.T. (Patrick), Eppinga, R.N. (Ruben N.), Felix, S.B. (Stephan), Guo, X. (Xiuqing), Hagemeijer, Y. (Yanick), Hansen, T. (T.), Harris, T.B. (Tamara), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Hwang, S.-J. (Shih-Jen), Kähönen, M. (Mika), Kanters, J.K., Kolcic, I. (Ivana), Launer, L.J. (Lenore), Li, M. (Man), Yao, J. (Jiefen), Linneberg, A. (Allan), Liu, S. (Simin), MacFarlane, P.W. (Peter), Mangino, M. (Massimo), Morris, A.D. (Andrew D.), Mulas, A. (Antonella), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Orrù, M. (Marco), Padmanabhan, S. (Sandosh), Peters, A. (Annette), Porteous, D.J. (David J.), Poulter, N.R. (Neil), Psaty, B.M. (Bruce M.), Qi, L. (Lihong), Raitakari, O.T. (Olli T.), Rivadeneira, F. (Fernando), Roselli, C. (Carolina), Rudan, I. (Igor), Sattar, N. (Naveed), Sever, P. (Peter), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed), Spector, T.D. (Timothy), Stanton, A. (Alice), Stirrups, K. (Kathy), Taylor, K.D. (Kent), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Hoes, A.W. (Arno), van der Meer, P. (Peter), Völker, U. (Uwe), Waldenberger, M. (Melanie), Xie, Z. (Zhijun), Zoledziewska, M. (Magdalena), Tinker, A. (Andrew), Polasek, O. (Ozren), Rosand, J. (Jonathan), Jamshidi, Y. (Yalda), Duijn, C.M. (Cornelia) van, Zeggini, E. (Eleftheria), Jukema, J.W. (Jan Wouter), Asselbergs, F.W. (Folkert), Samani, N.J. (Nilesh), Lehtimäki, T. (Terho), Gudnason, V. (Vilmundur), Wilson, J.F. (James), Lubitz, S.A. (Steven A.), Kääb, S. (Stefan), Sotoodehnia, N. (Nona), Caulfield, M. (Mark), Palmer, C.N.A. (Colin), Sanna, S. (Serena), Mook-Kanamori, D.O. (Dennis), Deloukas, P. (Panos), Pedersen, O. (Oluf), Rotter, J.I. (Jerome I.), Dörr, M. (Marcus), O'Donnell, C.J. (Christopher J.), Hayward, C. (Caroline), Arking, D.E. (Dan), Kooperberg, C. (Charles), van der Harst, P. (Pim), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), Munroe, P. (Patricia), Berg, M.E. (Marten) van den, Warren, H. (Helen), Cabrera, C.P. (Claudia P.), Verweij, N. (Niek), Mifsud, B. (Borbala), Haessler, J. (Jeff), Bihlmeyer, N.A. (Nathan A.), Fu, Y.-P. (Yi-Ping), Weiss, S. (Stefan), Lin, H.J. (Henry J.), Grarup, N. (Niels), Li-Gao, R. (Ruifang), Pistis, G. (Giorgio), Shah, N. (Nisha), Brody, J.A. (Jennifer A.), Müller-Nurasyid, M. (Martina), Lin, H. (Honghuang), Mei, H. (Hao), Smith, A.V. (Albert V.), Lyytikäinen, L.-P. (Leo-Pekka), Hall, L.M. (Leanne M.), Setten, J. (Jessica) van, Trompet, S. (Stella), Prins, B.P. (Bram P.), Isaacs, A.J. (Aaron), Radmanesh, F. (Farid), Marten, J. (Jonathan), Entwistle, A. (Aiman), Kors, J.A. (Jan), Silva Aldana, C.T. (Claudia), Alonso, A. (Alvaro), Bis, J.C. (Joshua), Boer, R.A. (Rudolf) de, Haan, H.G. (Hugoline) de, Mutsert, R. (Reneé) de, Dedoussis, G.V. (George), Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Ellinor, P.T. (Patrick), Eppinga, R.N. (Ruben N.), Felix, S.B. (Stephan), Guo, X. (Xiuqing), Hagemeijer, Y. (Yanick), Hansen, T. (T.), Harris, T.B. (Tamara), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Hwang, S.-J. (Shih-Jen), Kähönen, M. (Mika), Kanters, J.K., Kolcic, I. (Ivana), Launer, L.J. (Lenore), Li, M. (Man), Yao, J. (Jiefen), Linneberg, A. (Allan), Liu, S. (Simin), MacFarlane, P.W. (Peter), Mangino, M. (Massimo), Morris, A.D. (Andrew D.), Mulas, A. (Antonella), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Orrù, M. (Marco), Padmanabhan, S. (Sandosh), Peters, A. (Annette), Porteous, D.J. (David J.), Poulter, N.R. (Neil), Psaty, B.M. (Bruce M.), Qi, L. (Lihong), Raitakari, O.T. (Olli T.), Rivadeneira, F. (Fernando), Roselli, C. (Carolina), Rudan, I. (Igor), Sattar, N. (Naveed), Sever, P. (Peter), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed), Spector, T.D. (Timothy), Stanton, A. (Alice), Stirrups, K. (Kathy), Taylor, K.D. (Kent), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Hoes, A.W. (Arno), van der Meer, P. (Peter), Völker, U. (Uwe), Waldenberger, M. (Melanie), Xie, Z. (Zhijun), Zoledziewska, M. (Magdalena), Tinker, A. (Andrew), Polasek, O. (Ozren), Rosand, J. (Jonathan), Jamshidi, Y. (Yalda), Duijn, C.M. (Cornelia) van, Zeggini, E. (Eleftheria), Jukema, J.W. (Jan Wouter), Asselbergs, F.W. (Folkert), Samani, N.J. (Nilesh), Lehtimäki, T. (Terho), Gudnason, V. (Vilmundur), Wilson, J.F. (James), Lubitz, S.A. (Steven A.), Kääb, S. (Stefan), Sotoodehnia, N. (Nona), Caulfield, M. (Mark), Palmer, C.N.A. (Colin), Sanna, S. (Serena), Mook-Kanamori, D.O. (Dennis), Deloukas, P. (Panos), Pedersen, O. (Oluf), Rotter, J.I. (Jerome I.), Dörr, M. (Marcus), O'Donnell, C.J. (Christopher J.), Hayward, C. (Caroline), Arking, D.E. (Dan), Kooperberg, C. (Charles), van der Harst, P. (Pim), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), and Munroe, P. (Patricia)
Abstract: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
Published: 2017
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31. A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors

Author: Brænne, I. (Ingrid), Willenborg, C. (Christina), Tragante, V. (Vinicius), Kessler, T. (Thorsten), Zeng, L. (Lingyao), Reiz, B. (Benedikt), Kleinecke, M. (Mariana), Von Ameln, S. (Simon), Willer, C.J. (Cristen J.), Laakso, M. (Markku), Wild, P.S. (Philipp), Zeller, T. (Tanja), Wallentin, L. (Lars), Franks, P.W. (Paul), Salomaa, V. (Veikko), Dehghan, A. (Abbas), Meitinger, T. (Thomas), Samani, N.J. (Nilesh), Asselbergs, F.W. (Folkert), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Brænne, I. (Ingrid), Willenborg, C. (Christina), Tragante, V. (Vinicius), Kessler, T. (Thorsten), Zeng, L. (Lingyao), Reiz, B. (Benedikt), Kleinecke, M. (Mariana), Von Ameln, S. (Simon), Willer, C.J. (Cristen J.), Laakso, M. (Markku), Wild, P.S. (Philipp), Zeller, T. (Tanja), Wallentin, L. (Lars), Franks, P.W. (Paul), Salomaa, V. (Veikko), Dehghan, A. (Abbas), Meitinger, T. (Thomas), Samani, N.J. (Nilesh), Asselbergs, F.W. (Folkert), Erdmann, J. (Jeanette), and Schunkert, H. (Heribert)
Abstract: Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.
Published: 2017
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32. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Author: Brænne, I. (Ingrid), Zeng, L. (Lingyao), Willenborg, C. (Christina), Tragante, V. (Vinicius), Kessler, T. (Thorsten), Willer, C.J. (Cristen J.), Laakso, M. (Markku), Wallentin, L. (Lars), Franks, P.W. (Paul W.), Salomaa, V. (Veikko), Dehghan, A. (Abbas), Meitinger, T. (Thomas), Samani, N.J. (Nilesh J.), Asselbergs, F.W. (Folkert), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Brænne, I. (Ingrid), Zeng, L. (Lingyao), Willenborg, C. (Christina), Tragante, V. (Vinicius), Kessler, T. (Thorsten), Willer, C.J. (Cristen J.), Laakso, M. (Markku), Wallentin, L. (Lars), Franks, P.W. (Paul W.), Salomaa, V. (Veikko), Dehghan, A. (Abbas), Meitinger, T. (Thomas), Samani, N.J. (Nilesh J.), Asselbergs, F.W. (Folkert), Erdmann, J. (Jeanette), and Schunkert, H. (Heribert)
Abstract: Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.
Published: 2017
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33. Cardiorenal disease connection during post-menopause: The protective role of estrogen in uremic toxins induced microvascular dysfunction

Author: Pei, J. (Jiayi), Harakalova, M. (Magdalena), Ruijter, H.M. (Hester ) den, Pasterkamp, G. (Gerard), Duncker, D.J.G.M. (Dirk), Verhaar, M.C. (Marianne), Asselbergs, F.W. (Folkert), Cheng, C. (Caroline), Pei, J. (Jiayi), Harakalova, M. (Magdalena), Ruijter, H.M. (Hester ) den, Pasterkamp, G. (Gerard), Duncker, D.J.G.M. (Dirk), Verhaar, M.C. (Marianne), Asselbergs, F.W. (Folkert), and Cheng, C. (Caroline)
Abstract: Female gender, post-menopause, chronic kidney disease (CKD) and (CKD linked) microvascular disease are important risk factors for developing heart failure with preserved ejection fraction (HFpEF). Enhancing our understanding of the interrelation between these risk factors could greatly benefit the identification of new drug targets for future therapy. This review discusses the evidence for the protective role of estradiol (E2) in CKD-associated microvascular disease and related HFpEF. Elevated circulating levels of uremic toxins (UTs) during CKD may act in synergy with hormonal changes during post-menopause and could lead to coronary microvascular endothelial dysfunction in HFpEF. To elucidate the molecular mechanism involved, published transcriptome datasets of indoxyl sulfate (IS), high inorganic phosphate (HP) or E2 treated human derived endothelial cells from the NCBI Gene Expression Omnibus database were analyzed. In total, 36 genes overlapped in both IS- and HP-activated gene sets, 188 genes were increased by UTs (HP and/or IS) and decreased by E2, and 572 genes were decreased by UTs and increased by E2. Based on a comprehensive in silico analysis and literature studies of collected gene sets, we conclude that CKD-accumulated UTs could negatively impact renal and cardiac endothelial homeostasis by triggering extensive inflammatory responses and initiating dysregulation of angiogenesis. E2 may protect (myo)endothelium by inhibiting UTs-induced inflammation and ameliorating UTs-related uremic bleeding and thrombotic diathesis via restored coagulation capacity and hemostasis in injured vessels.
Published: 2017
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34. Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

Author: Van Der Laan, S.W. (Sander W.), Fall, M. (Magnus), Soumaré, A. (Aicha), Teumer, A. (Alexander), Sedaghat, S. (Sanaz), Baumert, J. (Jens), Zabaneh, D. (Delilah), Setten, J. (Jessica) van, Isgum, I. (Ivana), Galesloot, T.E. (Tessel), Arpegård, J. (Johannes), Amouyel, P. (Philippe), Trompet, S. (Stella), Waldenberger, M. (Melanie), Dörr, M. (Marcus), Magnusson, P.K. (Patrik), Giedraitis, V. (Vilmantas), Larsson, A. (Anders), Morris, A.P. (Andrew), Felix, J.F. (Janine), Morrison, A.C. (Alanna C.), Franceschini, N. (Nora), Bis, J.C. (Joshua), Kavousi, M. (Maryam), O'Donnell, C.J. (Christopher), Drenos, F. (Fotios), Tragante, V. (Vinicius), Munroe, P. (Patricia), Malik, R. (Rainer), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), Erdmann, J. (Jeanette), Nelson, C.P. (Christopher P.), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Marchini, J. (Jonathan), Patel, R.S. (Riyaz), Hingorani, A. (Aroon), Kao, W.H.L. (Wen), Pedersen, N.L. (Nancy), Graaf, J. (Jacqueline) de, Kiemeney, L.A.L.M. (Bart), Baumeister, S.E. (Sebastian), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Koenig, W. (Wolfgang), Meisinger, C. (Christa), Peters, A. (Annette), Thorand, B. (Barbara), Jukema, J.W. (Jan Wouter), Eriksen, B.O. (Bjørn Odvar), Toft, I. (Ingrid), Wilsgaard, T. (Tom), Onland-Moret, N.C. (N. Charlotte), Schouw, Y.T. (Yvonne) van der, Debette, S. (Stéphanie), Kumari, M. (Meena), Svensson, P. (Per), van der Harst, P. (Pim), Kivimaki, M. (Mika), Keating, J. (John), Sattar, N. (Naveed), Dehghan, A. (Abbas), Reiner, A. (Alexander), Ingelsson, E. (Erik), Ruijter, H.M. (Hester ) den, Bakker, P.I.W. (Paul) de, Pasterkamp, G. (Gerard), Ärnlöv, J. (Johan), Holmes, M.V. (Michael), Asselbergs, F.W. (Folkert), Van Der Laan, S.W. (Sander W.), Fall, M. (Magnus), Soumaré, A. (Aicha), Teumer, A. (Alexander), Sedaghat, S. (Sanaz), Baumert, J. (Jens), Zabaneh, D. (Delilah), Setten, J. (Jessica) van, Isgum, I. (Ivana), Galesloot, T.E. (Tessel), Arpegård, J. (Johannes), Amouyel, P. (Philippe), Trompet, S. (Stella), Waldenberger, M. (Melanie), Dörr, M. (Marcus), Magnusson, P.K. (Patrik), Giedraitis, V. (Vilmantas), Larsson, A. (Anders), Morris, A.P. (Andrew), Felix, J.F. (Janine), Morrison, A.C. (Alanna C.), Franceschini, N. (Nora), Bis, J.C. (Joshua), Kavousi, M. (Maryam), O'Donnell, C.J. (Christopher), Drenos, F. (Fotios), Tragante, V. (Vinicius), Munroe, P. (Patricia), Malik, R. (Rainer), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), Erdmann, J. (Jeanette), Nelson, C.P. (Christopher P.), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Marchini, J. (Jonathan), Patel, R.S. (Riyaz), Hingorani, A. (Aroon), Kao, W.H.L. (Wen), Pedersen, N.L. (Nancy), Graaf, J. (Jacqueline) de, Kiemeney, L.A.L.M. (Bart), Baumeister, S.E. (Sebastian), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Koenig, W. (Wolfgang), Meisinger, C. (Christa), Peters, A. (Annette), Thorand, B. (Barbara), Jukema, J.W. (Jan Wouter), Eriksen, B.O. (Bjørn Odvar), Toft, I. (Ingrid), Wilsgaard, T. (Tom), Onland-Moret, N.C. (N. Charlotte), Schouw, Y.T. (Yvonne) van der, Debette, S. (Stéphanie), Kumari, M. (Meena), Svensson, P. (Per), van der Harst, P. (Pim), Kivimaki, M. (Mika), Keating, J. (John), Sattar, N. (Naveed), Dehghan, A. (Abbas), Reiner, A. (Alexander), Ingelsson, E. (Erik), Ruijter, H.M. (Hester ) den, Bakker, P.I.W. (Paul) de, Pasterkamp, G. (Gerard), Ärnlöv, J. (Johan), Holmes, M.V. (Michael), and Asselbergs, F.W. (Folkert)
Abstract: __Background__ Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. __Objectives__ The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. __Methods__ We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. __Results__ Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10−14). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10−211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10−5). A causal effect of cystatin C was not detected for any individual component of CVD. __Conclusions__ Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
Published: 2016
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35. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

Author: Pankratz, V.S. (Shane), Schick, U.M. (Ursula), Zhou, Y. (Yi), Zhou, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Allende, M.L. (Maria Laura), Auer, P. (Paul), Bork-Jensen, J. (Jette), Brody, J.A. (Jennifer A.), Chen, M.-H. (Ming-Huei), Clavo, V. (Vinna), Eicher, J.D. (John D.), Grarup, N. (Niels), Hagedorn, E.J. (Elliott J.), Hu, B. (Bella), Hunker, K. (Kristina), Johnson, A.D. (Andrew), Leusink, M. (Maarten), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Marioni, R.E. (Riccardo), Nalls, M.A. (Michael), Pazoki, R. (Raha), Smith, A.V. (Albert Vernon), Rooij, F.J.A. (Frank) van, Yang, M.-L. (Min-Lee), Zhang, X. (Xiaoling), Zhang, Y. (Yan), Asselbergs, F.W. (Folkert), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bottinger, E.P. (Erwin), Cushman, M. (Mary Ann), Bakker, P.I.W. (Paul) de, Deary, I.J. (Ian), Dong, L. (Liguang), Feitosa, M.F. (Mary Furlan), Floyd, J. (James), Franceschini, N. (Nora), Franco, O.H. (Oscar), Garcia, M. (Melissa), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Hansen, T. (T.), Harris, T.B. (Tamara), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jia, J. (Jia), Kähönen, M. (Mika), Launer, L.J. (Lenore J.), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Nguyen, V.M. (Vy M.), Numans, M.E. (Mattijs), Pedersen, O. (Oluf), Psaty, B.M. (Bruce M.), Raitakari, O.T. (Olli T.), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Di Sant, A.M.R. (Amanda M. Rosa), Rotter, J.I. (Jerome I.), Starr, J.M. (John), Taylor, K.D. (Kent), Thuesen, B.H. (Betina Heinsbek), Tracy, R.P. (Russell), Uitterlinden, A.G. (André), Wang, J. (Jiansong), Wang, J. (Judy), Dehghan, A. (Abbas), Huo, Y. (Yong), Cupples, L.A. (Adrienne), Wilson, J.F. (James), Proia, R.L. (Richard L.), Zon, L.I. (Leonard), O'Donnell, C.J. (Christopher), Reiner, A.P. (Alex P.), Ganesh, S.K. (Santhi), Pankratz, V.S. (Shane), Schick, U.M. (Ursula), Zhou, Y. (Yi), Zhou, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Allende, M.L. (Maria Laura), Auer, P. (Paul), Bork-Jensen, J. (Jette), Brody, J.A. (Jennifer A.), Chen, M.-H. (Ming-Huei), Clavo, V. (Vinna), Eicher, J.D. (John D.), Grarup, N. (Niels), Hagedorn, E.J. (Elliott J.), Hu, B. (Bella), Hunker, K. (Kristina), Johnson, A.D. (Andrew), Leusink, M. (Maarten), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Marioni, R.E. (Riccardo), Nalls, M.A. (Michael), Pazoki, R. (Raha), Smith, A.V. (Albert Vernon), Rooij, F.J.A. (Frank) van, Yang, M.-L. (Min-Lee), Zhang, X. (Xiaoling), Zhang, Y. (Yan), Asselbergs, F.W. (Folkert), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bottinger, E.P. (Erwin), Cushman, M. (Mary Ann), Bakker, P.I.W. (Paul) de, Deary, I.J. (Ian), Dong, L. (Liguang), Feitosa, M.F. (Mary Furlan), Floyd, J. (James), Franceschini, N. (Nora), Franco, O.H. (Oscar), Garcia, M. (Melissa), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Hansen, T. (T.), Harris, T.B. (Tamara), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jia, J. (Jia), Kähönen, M. (Mika), Launer, L.J. (Lenore J.), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Nguyen, V.M. (Vy M.), Numans, M.E. (Mattijs), Pedersen, O. (Oluf), Psaty, B.M. (Bruce M.), Raitakari, O.T. (Olli T.), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Di Sant, A.M.R. (Amanda M. Rosa), Rotter, J.I. (Jerome I.), Starr, J.M. (John), Taylor, K.D. (Kent), Thuesen, B.H. (Betina Heinsbek), Tracy, R.P. (Russell), Uitterlinden, A.G. (André), Wang, J. (Jiansong), Wang, J. (Judy), Dehghan, A. (Abbas), Huo, Y. (Yong), Cupples, L.A. (Adrienne), Wilson, J.F. (James), Proia, R.L. (Richard L.), Zon, L.I. (Leonard), O'Donnell, C.J. (Christopher), Reiner, A.P. (Alex P.), and Ganesh, S.K. (Santhi)
Abstract: Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
Published: 2016
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36. PCSK9 genetic variants and risk of type 2 diabetes: A mendelian randomisation study

Author: Schmidt, A.F. (Amand F.), Swerdlow, D.I. (Daniel), Holmes, M.V. (Michael), Patel, R.S. (Riyaz), Fairhurst-Hunter, Z. (Zammy), Lyall, D.M. (Donald M.), Hartwig, F.P. (Fernando Pires), Horta, B.L. (Bernardo Lessa), Hypponen, E. (Elina), Power, C. (Christopher), Moldovan, M. (Max), Iperen, E.P.A. (Erik) van, Hovingh, G.K. (Kees), Demuth, I. (Ilja), Norman, K. (Kristina), Steinhagen-Thiessen, E. (Elisabeth), Demuth, J. (Juri), Bertram, L. (Lars), Liu, T. (Tian), Coassin, S. (Stefan), Willeit, J. (Johann), Kiechl, S. (Stefan), Willeit, K. (Karin), Mason, D. (Dan), Wright, J. (Juliet), Morris, R.W. (Richard), Wanamethee, G. (Goya), Whincup, P.H. (Peter), Ben-Shlomo, Y., McLachlan, S. (Stela), Price, J.F. (Jackie F.), Kivimaki, M. (Mika), Welch, C. (Catherine), Sanchez-Galvez, A. (Adelaida), Marques-Vidal, P. (Pedro), Nicolaides, A.N. (Andrew), Panayiotou, A.G. (Andrie), Onland-Moret, N.C. (N Charlotte), Schouw, Y.T. (Yvonne) van der, Matullo, G., Fiorito, G. (Giovanni), Guarrera, S. (Simonetta), Sacerdote, C. (Carlotta), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Scott, R. (Robert), Luan, J. (Jian'an), Bobak, M. (Martin), Malyutina, S., Pajak, A. (Andrzej), Kubinova, R., Tamosiunas, A. (Abdonas), Pikhart, H. (Hynek), Husemoen, L.L.N. (Lise Lotte), Grarup, N. (Niels), Pedersen, O. (Oluf), Hansen, T. (T.), Linneberg, A. (Allan), Simonsen, K.S. (Kenneth Starup), Cooper, J. (Jim), Humphries, S.E. (Steve), Brilliant, M.H. (Murray H.), Kitchner, T.E. (Terrie E.), Hakonarson, H. (Hakon), Carrell, D.S. (David), McCarty, C.A. (Catherine A.), Kirchner, H.L. (H Lester), Larson, E.B. (Eric B.), Crosslin, D.R. (David), de Andrade, M. (Mariza), Roden, D.M. (Dan M.), Denny, J.C. (Joshua C.), Carty, C. (Cara), Hancock, S. (Stephen), Attia, J. (John), Holliday, E.G. (Elizabeth), Donnell, M.O.'. (Martin O'), Yusuf, S. (Salim), Chong, M. (Michael), Pare, G. (Guillame), Harst, P. (Pim) van der, Said, M.A. (M Abdullah), Eppinga, R.N. (Ruben N.), Verweij, N. (Niek), Snieder, H. (Harold), Christen, T. (Tim), Mook-Kanamori, D.O. (Dennis), Gustafsson, S. (Stefan), Kao, W.H.L. (Wen), Ingelsson, E. (Erik), Pazoki, R. (Raha), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Dehghan, A. (Abbas), Teumer, A. (Alexander), Baumeister, S.E. (Sebastian), Dörr, M. (Marcus), Lerch, M.M. (Markus M.), Völker, U. (Uwe), Völzke, H. (Henry), Ward, J. (Joey), Pell, J.P. (Jill P.), Smith, D.J. (Daniel J.), Meade, T. (Tom), Maitland-van der Zee, A-H. (Anke-Hilse), Baranova, E.V. (Ekaterina V.), Young, R. (Robin), Ford, I. (Ian), Campbell, A. (Archie), Padmanabhan, S. (Sandosh), Bots, M.L. (Michiel), Grobbee, D.E. (Diederick E.), Froguel, P. (Philippe), Thuillier, D. (Dorothee), Balkau, B. (Beverley), Bonnefond, A. (Amélie), Cariou, B. (Bertrand), Smart, M. (Melissa), Bao, Y. (Yanchun), Kumari, M. (Meena), Mahajan, A. (Anubha), Ridker, P.M. (Paul), Chasman, D.I. (Daniel I.), Reiner, A. (Alexander), Lange, L.A. (Leslie), Ritchie, M.D. (Marylyn D.), Asselbergs, F.W. (Folkert), Casas, J.P. (Juan), Keating, J. (John), Preiss, D. (David), Hingorani, A. (Aroon), Sattar, N. (Naveed), Schmidt, A.F. (Amand F.), Swerdlow, D.I. (Daniel), Holmes, M.V. (Michael), Patel, R.S. (Riyaz), Fairhurst-Hunter, Z. (Zammy), Lyall, D.M. (Donald M.), Hartwig, F.P. (Fernando Pires), Horta, B.L. (Bernardo Lessa), Hypponen, E. (Elina), Power, C. (Christopher), Moldovan, M. (Max), Iperen, E.P.A. (Erik) van, Hovingh, G.K. (Kees), Demuth, I. (Ilja), Norman, K. (Kristina), Steinhagen-Thiessen, E. (Elisabeth), Demuth, J. (Juri), Bertram, L. (Lars), Liu, T. (Tian), Coassin, S. (Stefan), Willeit, J. (Johann), Kiechl, S. (Stefan), Willeit, K. (Karin), Mason, D. (Dan), Wright, J. (Juliet), Morris, R.W. (Richard), Wanamethee, G. (Goya), Whincup, P.H. (Peter), Ben-Shlomo, Y., McLachlan, S. (Stela), Price, J.F. (Jackie F.), Kivimaki, M. (Mika), Welch, C. (Catherine), Sanchez-Galvez, A. (Adelaida), Marques-Vidal, P. (Pedro), Nicolaides, A.N. (Andrew), Panayiotou, A.G. (Andrie), Onland-Moret, N.C. (N Charlotte), Schouw, Y.T. (Yvonne) van der, Matullo, G., Fiorito, G. (Giovanni), Guarrera, S. (Simonetta), Sacerdote, C. (Carlotta), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Scott, R. (Robert), Luan, J. (Jian'an), Bobak, M. (Martin), Malyutina, S., Pajak, A. (Andrzej), Kubinova, R., Tamosiunas, A. (Abdonas), Pikhart, H. (Hynek), Husemoen, L.L.N. (Lise Lotte), Grarup, N. (Niels), Pedersen, O. (Oluf), Hansen, T. (T.), Linneberg, A. (Allan), Simonsen, K.S. (Kenneth Starup), Cooper, J. (Jim), Humphries, S.E. (Steve), Brilliant, M.H. (Murray H.), Kitchner, T.E. (Terrie E.), Hakonarson, H. (Hakon), Carrell, D.S. (David), McCarty, C.A. (Catherine A.), Kirchner, H.L. (H Lester), Larson, E.B. (Eric B.), Crosslin, D.R. (David), de Andrade, M. (Mariza), Roden, D.M. (Dan M.), Denny, J.C. (Joshua C.), Carty, C. (Cara), Hancock, S. (Stephen), Attia, J. (John), Holliday, E.G. (Elizabeth), Donnell, M.O.'. (Martin O'), Yusuf, S. (Salim), Chong, M. (Michael), Pare, G. (Guillame), Harst, P. (Pim) van der, Said, M.A. (M Abdullah), Eppinga, R.N. (Ruben N.), Verweij, N. (Niek), Snieder, H. (Harold), Christen, T. (Tim), Mook-Kanamori, D.O. (Dennis), Gustafsson, S. (Stefan), Kao, W.H.L. (Wen), Ingelsson, E. (Erik), Pazoki, R. (Raha), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Dehghan, A. (Abbas), Teumer, A. (Alexander), Baumeister, S.E. (Sebastian), Dörr, M. (Marcus), Lerch, M.M. (Markus M.), Völker, U. (Uwe), Völzke, H. (Henry), Ward, J. (Joey), Pell, J.P. (Jill P.), Smith, D.J. (Daniel J.), Meade, T. (Tom), Maitland-van der Zee, A-H. (Anke-Hilse), Baranova, E.V. (Ekaterina V.), Young, R. (Robin), Ford, I. (Ian), Campbell, A. (Archie), Padmanabhan, S. (Sandosh), Bots, M.L. (Michiel), Grobbee, D.E. (Diederick E.), Froguel, P. (Philippe), Thuillier, D. (Dorothee), Balkau, B. (Beverley), Bonnefond, A. (Amélie), Cariou, B. (Bertrand), Smart, M. (Melissa), Bao, Y. (Yanchun), Kumari, M. (Meena), Mahajan, A. (Anubha), Ridker, P.M. (Paul), Chasman, D.I. (Daniel I.), Reiner, A. (Alexander), Lange, L.A. (Leslie), Ritchie, M.D. (Marylyn D.), Asselbergs, F.W. (Folkert), Casas, J.P. (Juan), Keating, J. (John), Preiss, D. (David), Hingorani, A. (Aroon), and Sattar, N. (Naveed)
Abstract: Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering . PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). Interpretation: . PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibi
Published: 2016
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37. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author: Surendran, P. (Praveen), Drenos, F. (Fotios), Young, R. (Robin), Warren, H. (Helen), Cook, J.P. (James P.), Manning, A.K. (Alisa), Grarup, N. (Niels), Sim, X. (Xueling), Barnes, D. (Daniel), Witkowska, H.E. (Ewa), Staley, J.R. (James R.), Tragante, V. (Vinicius), Tukiainen, T. (Taru), Yaghootkar, H. (Hanieh), Masca, N. (Nicholas), Freitag, C.M. (Christine), Ferreira, T. (Teresa), Giannakopoulou, O. (Olga), Tinker, A. (Andrew), Harakalova, M. (Magdalena), Mihailov, E. (Evelin), Liu, C. (Chunyu), Kraja, A. (Aldi), Nielsen, S.F. (Sune), Rasheed, A. (Asif), Samuel, M. (Maria), Zhao, W. (Wei), Bonnycastle, L.L. (Lori), Jackson, A.U. (Anne), Narisu, N. (Narisu), Swift, A.J. (Amy), Southam, L. (Lorraine), Marten, J. (Jonathan), Huyghe, J.R. (Jeroen R.), Stancáková, A. (Alena), Fava, C. (Cristiano), Ohlsson, T. (Therese), Matchan, A. (Angela), Stirrups, K. (Kathy), Bork-Jensen, J. (Jette), Gjesing, A.P. (Anette), Kontto, J. (Jukka), Perola, M. (Markus), Shaw-Hawkins, S. (Sue), Havulinna, A.S. (Aki), Zhang, H. (He), Donnelly, L.A. (Louise), Groves, C.J. (Christopher), Rayner, N.W. (Nigel William), Neville, M.J. (Matthew), Robertson, N.R. (Neil), Yiorkas, A.M. (Andrianos M.), Herzig, K.H., Kajantie, E. (Eero), Zhang, W. (Weihua), Willems, S.M. (Sara), Lannfelt, L. (Lars), Malerba, G. (Giovanni), Soranzo, N. (Nicole), Trabetti, E. (Elisabetta), Verweij, N. (Niek), Evangelou, E. (Evangelos), Moayyeri, A. (Alireza), Vergnaud, A.-C. (Anne-Claire), Nelson, C.P. (Christopher P.), Poveda, A. (Alaitz), Varga, T.V. (Tibor V.), Caslake, M. (Muriel), De Craen, A.J.M. (Anton J. M.), Trompet, S. (Stella), Luan, J. (Jian'An), Scott, R.A. (Robert), Harris, S.E. (Sarah), Liewald, D.C.M. (David), Marioni, R.E. (Riccardo), Menni, C. (Cristina), Farmaki, A.-E. (Aliki-Eleni), Hallmans, G. (Göran), Renström, F. (Frida), Huffman, J.E. (Jennifer), Hassinen, M. (Maija), Burgess, S. (Stephen), Vasan, R.S. (Ramachandran S.), Felix, J.F. (Janine), Uria-Nickelsen, M. (Maria), Mälarstig, A. (Anders), Reilly, D.F. (Dermot F.), Hoek, M. (Maarten), Vogt, T.F. (Thomas F.), Lin, H. (Honghuang), Lieb, W. (Wolfgang), Traylor, M. (Matthew), Markus, H.S. (Hugh), Highland, H. (Heather), Justice, A.E. (Anne), Marouli, E. (Eirini), Lindström, J. (Jaana), Uusitupa, M. (Matti), Komulainen, P. (Pirjo), Lakka, T.A. (Timo), Rauramaa, R. (Rainer), Polasek, O. (Ozren), Rudan, I. (Igor), Rolandsson, O. (Olov), Franks, P.W. (Paul), Dedoussis, G.V. (George), Spector, T.D. (Timothy), Jousilahti, P. (Pekka), Männistö, S. (Satu), Deary, I.J. (Ian), Starr, J.M. (John), Langenberg, C. (Claudia), Wareham, N.J. (Nick), Brown, M.J. (Morris), Dominiczak, A. (Anna), Connell, J.M. (John M.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Ford, I. (Ian), Packard, C.J. (Chris J.), Esko, T. (Tõnu), Mägi, R. (Reedik), Metspalu, A. (Andres), Boer, R.A. (Rudolf) de, Van Der Meer, P. (Peter), Harst, P. (Pim) van der, Gambaro, G. (Giovanni), Ingelsson, E. (Erik), Kao, W.H.L. (Wen), Bakker, P.I.W. (Paul) de, Numans, M.E. (Mattijs), Brandslund, I. (Ivan), Christensen, C. (Cramer), Petersen, E.R.B. (Eva R. B.), Korpi-Hyövälti, E. (Eeva), Oksa, H. (Heikki), Chambers, J.C. (John), Kooner, J.S. (Jaspal S.), Blakemore, A.I.F. (Alexandra), Franks, S. (Steve), Jarvelin, M.-R. (Marjo-Riitta), Husemoen, L.L.N. (Lise Lotte), Linneberg, A. (Allan), Skaaby, T. (Tea), Thuesen, B. (Betina), Karpe, F. (Fredrik), Tuomilehto, J. (Jaakko), Doney, A.S.F. (Alex), Morris, A.D. (Andrew), Palmer, C.N.A. (Colin), Holmen, O.L. (Oddgeir), Hveem, K. (Kristian), Willer, C.J. (Cristen), Tuomi, T. (Tiinamaija), Groop, L. (Leif), Käräjämäki, A. (Annemari), Palotie, A. (Aarno), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Alam, D.S. (Dewan S.), Majumder, A.A.S. (Abdulla Al Shafi), Angelantonio, E. (Emanuele) di, Chowdhury, R. (Rajiv), McCarthy, M.I. (Mark), Poulter, N.R. (Neil), Stanton, A. (Alice), Sever, P. (Peter), Amouyel, P. (Philippe), Arveiler, D. (Dominique), Blankenberg, S. (Stefan), Ferrieres, J. (Jean), Kee, F. (Frank), Kuulasmaa, K. (Kari), Müller-Nurasyid, M. (Martina), Veronesi, G. (Giovanni), Virtamo, J. (Jarmo), Deloukas, P. (Panagiotis), Elliott, P. (Paul), Zeggini, E. (Eleftheria), Kathiresan, S. (Sekar), Melander, O. (Olle), Kuusisto, J. (Johanna), Laakso, M. (Markku), Padmanabhan, S. (Sandosh), Porteous, D. (David), Hayward, C. (Caroline), Scotland, G. (Generation), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Hansen, T. (T.), Pedersen, O. (Oluf), Boehnke, M. (Michael), Stringham, H.M. (Heather), Frossard, R., Newton-Cheh, C. (Christopher), Tobin, M.D. (Martin), Nordestgaard, B.G. (Børge), Caulfield, M. (Mark), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Tomaszewski, M. (Maciej), Samani, N.J. (Nilesh), Saleheen, D. (Danish), Asselbergs, F.W. (Folkert), Lindgren, C.M. (Cecilia M.), Danesh, J. (John), Wain, L.V. (Louise V.), Butterworth, A.S. (Adam), Howson, J.M.M. (Joanna M. M.), Munroe, P. (Patricia), Surendran, P. (Praveen), Drenos, F. (Fotios), Young, R. (Robin), Warren, H. (Helen), Cook, J.P. (James P.), Manning, A.K. (Alisa), Grarup, N. (Niels), Sim, X. (Xueling), Barnes, D. (Daniel), Witkowska, H.E. (Ewa), Staley, J.R. (James R.), Tragante, V. (Vinicius), Tukiainen, T. (Taru), Yaghootkar, H. (Hanieh), Masca, N. (Nicholas), Freitag, C.M. (Christine), Ferreira, T. (Teresa), Giannakopoulou, O. (Olga), Tinker, A. (Andrew), Harakalova, M. (Magdalena), Mihailov, E. (Evelin), Liu, C. (Chunyu), Kraja, A. (Aldi), Nielsen, S.F. (Sune), Rasheed, A. (Asif), Samuel, M. (Maria), Zhao, W. (Wei), Bonnycastle, L.L. (Lori), Jackson, A.U. (Anne), Narisu, N. (Narisu), Swift, A.J. (Amy), Southam, L. (Lorraine), Marten, J. (Jonathan), Huyghe, J.R. (Jeroen R.), Stancáková, A. (Alena), Fava, C. (Cristiano), Ohlsson, T. (Therese), Matchan, A. (Angela), Stirrups, K. (Kathy), Bork-Jensen, J. (Jette), Gjesing, A.P. (Anette), Kontto, J. (Jukka), Perola, M. (Markus), Shaw-Hawkins, S. (Sue), Havulinna, A.S. (Aki), Zhang, H. (He), Donnelly, L.A. (Louise), Groves, C.J. (Christopher), Rayner, N.W. (Nigel William), Neville, M.J. (Matthew), Robertson, N.R. (Neil), Yiorkas, A.M. (Andrianos M.), Herzig, K.H., Kajantie, E. (Eero), Zhang, W. (Weihua), Willems, S.M. (Sara), Lannfelt, L. (Lars), Malerba, G. (Giovanni), Soranzo, N. (Nicole), Trabetti, E. (Elisabetta), Verweij, N. (Niek), Evangelou, E. (Evangelos), Moayyeri, A. (Alireza), Vergnaud, A.-C. (Anne-Claire), Nelson, C.P. (Christopher P.), Poveda, A. (Alaitz), Varga, T.V. (Tibor V.), Caslake, M. (Muriel), De Craen, A.J.M. (Anton J. M.), Trompet, S. (Stella), Luan, J. (Jian'An), Scott, R.A. (Robert), Harris, S.E. (Sarah), Liewald, D.C.M. (David), Marioni, R.E. (Riccardo), Menni, C. (Cristina), Farmaki, A.-E. (Aliki-Eleni), Hallmans, G. (Göran), Renström, F. (Frida), Huffman, J.E. (Jennifer), Hassinen, M. (Maija), Burgess, S. (Stephen), Vasan, R.S. (Ramachandran S.), Felix, J.F. (Janine), Uria-Nickelsen, M. (Maria), Mälarstig, A. (Anders), Reilly, D.F. (Dermot F.), Hoek, M. (Maarten), Vogt, T.F. (Thomas F.), Lin, H. (Honghuang), Lieb, W. (Wolfgang), Traylor, M. (Matthew), Markus, H.S. (Hugh), Highland, H. (Heather), Justice, A.E. (Anne), Marouli, E. (Eirini), Lindström, J. (Jaana), Uusitupa, M. (Matti), Komulainen, P. (Pirjo), Lakka, T.A. (Timo), Rauramaa, R. (Rainer), Polasek, O. (Ozren), Rudan, I. (Igor), Rolandsson, O. (Olov), Franks, P.W. (Paul), Dedoussis, G.V. (George), Spector, T.D. (Timothy), Jousilahti, P. (Pekka), Männistö, S. (Satu), Deary, I.J. (Ian), Starr, J.M. (John), Langenberg, C. (Claudia), Wareham, N.J. (Nick), Brown, M.J. (Morris), Dominiczak, A. (Anna), Connell, J.M. (John M.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Ford, I. (Ian), Packard, C.J. (Chris J.), Esko, T. (Tõnu), Mägi, R. (Reedik), Metspalu, A. (Andres), Boer, R.A. (Rudolf) de, Van Der Meer, P. (Peter), Harst, P. (Pim) van der, Gambaro, G. (Giovanni), Ingelsson, E. (Erik), Kao, W.H.L. (Wen), Bakker, P.I.W. (Paul) de, Numans, M.E. (Mattijs), Brandslund, I. (Ivan), Christensen, C. (Cramer), Petersen, E.R.B. (Eva R. B.), Korpi-Hyövälti, E. (Eeva), Oksa, H. (Heikki), Chambers, J.C. (John), Kooner, J.S. (Jaspal S.), Blakemore, A.I.F. (Alexandra), Franks, S. (Steve), Jarvelin, M.-R. (Marjo-Riitta), Husemoen, L.L.N. (Lise Lotte), Linneberg, A. (Allan), Skaaby, T. (Tea), Thuesen, B. (Betina), Karpe, F. (Fredrik), Tuomilehto, J. (Jaakko), Doney, A.S.F. (Alex), Morris, A.D. (Andrew), Palmer, C.N.A. (Colin), Holmen, O.L. (Oddgeir), Hveem, K. (Kristian), Willer, C.J. (Cristen), Tuomi, T. (Tiinamaija), Groop, L. (Leif), Käräjämäki, A. (Annemari), Palotie, A. (Aarno), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Alam, D.S. (Dewan S.), Majumder, A.A.S. (Abdulla Al Shafi), Angelantonio, E. (Emanuele) di, Chowdhury, R. (Rajiv), McCarthy, M.I. (Mark), Poulter, N.R. (Neil), Stanton, A. (Alice), Sever, P. (Peter), Amouyel, P. (Philippe), Arveiler, D. (Dominique), Blankenberg, S. (Stefan), Ferrieres, J. (Jean), Kee, F. (Frank), Kuulasmaa, K. (Kari), Müller-Nurasyid, M. (Martina), Veronesi, G. (Giovanni), Virtamo, J. (Jarmo), Deloukas, P. (Panagiotis), Elliott, P. (Paul), Zeggini, E. (Eleftheria), Kathiresan, S. (Sekar), Melander, O. (Olle), Kuusisto, J. (Johanna), Laakso, M. (Markku), Padmanabhan, S. (Sandosh), Porteous, D. (David), Hayward, C. (Caroline), Scotland, G. (Generation), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Hansen, T. (T.), Pedersen, O. (Oluf), Boehnke, M. (Michael), Stringham, H.M. (Heather), Frossard, R., Newton-Cheh, C. (Christopher), Tobin, M.D. (Martin), Nordestgaard, B.G. (Børge), Caulfield, M. (Mark), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Tomaszewski, M. (Maciej), Samani, N.J. (Nilesh), Saleheen, D. (Danish), Asselbergs, F.W. (Folkert), Lindgren, C.M. (Cecilia M.), Danesh, J. (John), Wain, L.V. (Louise V.), Butterworth, A.S. (Adam), Howson, J.M.M. (Joanna M. M.), and Munroe, P. (Patricia)
Abstract: High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
Published: 2016
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38. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author: Winkler, T.W. (Thomas W.), Justice, A.E. (Anne), Graff, M.J. (Maud J.L.), Barata, L. (Llilda), Feitosa, M.F. (Mary Furlan), Chu, S. (Su), Czajkowski, J. (Jacek), Esko, T. (Tõnu), Fall, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Lu, Y. (Yingchang), Mägi, R. (Reedik), Mihailov, E. (Evelin), Pers, T.H. (Tune), Rüeger, S. (Sina), Teumer, A. (Alexander), Ehret, G.B. (Georg), Ferreira, T. (Teresa), Heard-Costa, N.L. (Nancy), Karjalainen, J. (Juha), Lagou, V. (Vasiliki), Mahajan, A. (Anubha), Neinast, M.D. (Michael D.), Prokopenko, I. (Inga), Simino, J. (Jeannette), Teslovich, T.M. (Tanya M.), Jansen, R., Westra, H.J. (Harm-Jan), White, C.C. (Charles), Absher, D. (Devin), Ahluwalia, T.S. (Tarunveer Singh), Ahmad, S. (Shafqat), Albrecht, E. (Eva), Alves, A.C. (Alexessander Couto), Bragg-Gresham, J.L. (Jennifer L.), Craen, A.J. (Anton) de, Bis, J.C. (Joshua), Bonnefond, A. (Amélie), Boucher, G. (Gabrielle), Cadby, G. (Gemma), Cheng, Y.-C. (Yu-Ching), Chiang, C.W. (Charleston W K), Delgado, G., Demirkan, A. (Ayşe), Dueker, N. (Nicole), Eklund, N. (Niina), Eiriksdottir, G. (Gudny), Eriksson, J. (Joel), Feenstra, B. (Bjarke), Fischer, K. (Krista), Frau, F. (Francesca), Galesloot, T.E. (Tessel), Geller, F. (Frank), Goel, A. (Anuj), Gorski, M. (Mathias), Grammer, T.B. (Tanja), Gustafsson, S. (Stefan), Haitjema, S. (Saskia), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Jacobs, K.B. (Kevin), Johansson, A. (Åsa), Kaakinen, M. (Marika), Kleber, M.E. (Marcus), Lahti, J. (Jari), Leach, I.M. (Irene Mateo), Lehne, B. (Benjamin), Liu, Y. (Youfang), Lo, K.S., Lorentzon, M. (Mattias), Luan, J. (Jian'An), Madden, P.A. (Pamela), Mangino, M. (Massimo), McKnight, B. (Barbara), Medina-Gomez, C. (Carolina), Monda, K.L. (Keri), Montasser, M.E. (May E.), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Panoutsopoulou, K. (Kalliope), Pascoe, L. (Laura), Paternoster, L. (Lavinia), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rizzi, F. (Federica), Rose, L.M. (Lynda), Ryan, K.A. (Kathy A.), Salo, P. (Perttu), Sanna, S. (Serena), Scharnagl, H. (Hubert), Shi, J. (Jianxin), Smith, A.V. (Albert Vernon), Southam, L. (Lorraine), Stancáková, A. (Alena), Steinthorsdottir, V. (Valgerdur), Strawbridge, R.J. (Rona), Sung, Y.J. (Yun Ju), Tachmazidou, I. (Ioanna), Tanaka, T. (Toshiko), Thorleifsson, G. (Gudmar), Trompet, S. (Stella), Pervjakova, N. (Natalia), Tyrer, J.P. (Jonathan), Vandenput, L. (Liesbeth), Van Der Laan, S.W. (Sander W.), Velde, N. (Nathalie) van der, Setten, J. (Jessica) van, Vliet-Ostaptchouk, J.V. (Jana) van, Verweij, N. (Niek), Vlachopoulou, E. (Efthymia), Waite, L. (Lindsay), Wang, S.R. (Sophie), Wang, Z. (Zhaoming), Wild, S.H. (Sarah), Willenborg, C. (Christina), Wilson, J.F. (James), Wong, A. (Andrew), Yang, J. (Jian), Yengo, L. (Loic), Yerges-Armstrong, L.M. (Laura), Yu, L. (Lei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Andersson, E.A. (Ehm Astrid), Bakker, S.J.L. (Stephan), Baldassarre, D. (Damiano), Banasik, K. (Karina), Barcella, M. (Matteo), Barlassina, C. (Cristina), Bellis, C. (Claire), Benaglio, P. (Paola), Blangero, J. (John), Blüher, M. (Matthias), Bonnet, F. (Fabrice), Bonnycastle, L.L. (Lori), Boyd, H.A. (Heather), Bruinenberg, M. (M.), Buchman, A.S. (Aron S.), Campbell, H. (Harry), Chen, Y.D. (Y.), Chines, P.S. (Peter), Claudi-Boehm, S. (Simone), Cole, J.W. (John W.), Collins, F.S. (Francis), Geus, E.J.C. (Eco) de, Groot, L.C.P.G.M. (Lisette) de, Dimitriou, M. (Maria), Duan, J. (Jubao), Enroth, S. (Stefan), Eury, E. (Elodie), Farmaki, A.-E. (Aliki-Eleni), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gejman, P.V. (Pablo), Gigante, B. (Bruna), Glorioso, N. (Nicola), Go, A.T.J.I. (Attie), Gottesman, R.F. (Rebecca), Gräßler, J. (Jürgen), Grallert, H. (Harald), Grarup, N. (Niels), Gu, Y.-M. (Yu-Mei), Broer, L. (Linda), Ham, A.C. (Annelies), Hansen, T. (T.), Harris, T.B. (Tamara), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Heath, A.C. (Andrew), Henders, A.K. (Anjali), Hernandez, D.G. (Dena), Hillege, H.L. (Hans), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Hui, J. (Jennie), Husemoen, L.L. (Lise L.), Hutri-Kähönen, N. (Nina), Hysi, P.G. (Pirro), Illig, T. (Thomas), Jager, P.L. (Philip) de, Jalilzadeh, S. (Shapour), Jorgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Juonala, M. (Markus), Kanoni, S. (Stavroula), Karaleftheri, M. (Maria), Khaw, K.T., Kinnunen, L. (Leena), Kittner, T. (Thomas), Koenig, W. (Wolfgang), Kolcic, I. (Ivana), Kovacs, P. (Peter), Krarup, N.T. (Nikolaj T.), Kratzer, W. (Wolfgang), Krüger, J. (Janine), Kuh, D. (Diana), Kumari, M. (Meena), Kyriakou, T. (Theodosios), Langenberg, C. (Claudia), Lannfelt, L. (Lars), Lanzani, C. (Chiara), Lotay, V. (Vaneet), Launer, L.J. (Lenore), Leander, K. (Karin), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y.-P. (Yan-Ping), Lobbens, S. 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(Amy), Syvänen, A.C., Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Tönjes, A. (Anke), Tremblay, A. (Angelo), Tsafantakis, E. (Emmanouil), Most, P.J. (Peter) van der, Völker, U. (Uwe), Vohl, M.-C. (Marie-Claude), Vonk, J.M. (Judith), Waldenberger, M. (Melanie), Walker, R.W. (Ryan W.), Wennauer, R. (Roman), Widen, E., Willemsen, G.A.H.M. (Gonneke), Wilsgaard, T. (Tom), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Van Dijk, S. (Suzanne), Schoor, N.M. (Natasja) van, Asselbergs, F.W. (Folkert), Bakker, P.I.W. (Paul) de, Beckmann, J.S. (Jacques), Beilby, J.P. (John), Bennett, D.A. (David A.), Bergman, R.N. (Richard), Bergmann, S.M. (Sven), Böger, C.A. (Carsten), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Bornstein, S.R. (Stefan), Bottinger, E.P. (Erwin), Bouchard, C. (Claude), Chambers, J.C. (John), Chanock, S.J. (Stephen), Chasman, D.I. (Daniel), Cucca, F. (Francesco), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Hagen, K. 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(Douglas), Kao, W.H.L. (Wen), Lokki, M.L., Mäntyselkä, P. (Pekka), Melbye, M. (Mads), Metspalu, A. (Andres), Mitchell, B.D. (Braxton), Moll, F.L. (Frans), Murray, J.C. (Jeffrey), Musk, A.W. (Arthur), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), Palmer, C. (Cameron), Pankow, J.S. (James), Pasterkamp, G. (Gerard), Pedersen, N.L. (Nancy), Pedersen, O. (Oluf), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce M.), Qi, L. (Lu), Quertermous, T. (Thomas), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Rioux, J.D. (John), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Saltevo, J. (Juha), Sattar, N. (Naveed), Schunkert, H. (Heribert), Schwarz, P.E.H. (Peter), Shuldiner, A.R. (Alan), Sinisalo, J. (Juha), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Staessen, J.A. (Jan A.), Stefania, B. (Bandinelli), Thorsteinsdottir, U. (Unnur), Stumvoll, M. (Michael), Tardif, J.-C. (Jean-Claude), Tremoli, E. (Elena), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Verbeek, A.L.M., Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Vitart, V. (Veronique), Völzke, H. (Henry), Vollenweider, P. (Peter), Waeber, G. (Gérard), Walker, M. (Mark), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Zeggini, E. (Eleftheria), Chakravarti, A. (Aravinda), Clegg, D.J. (Deborah J.), Cupples, L.A. (Adrienne), Gordon-Larsen, P. (Penny), Jaquish, C.E. (Cashell), Rao, D.C. (Dabeeru C.), Abecasis, G.R. (Goncalo R.), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Berndt, S.I. (Sonja), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C.S. (Caroline), Groop, L. (Leif), Hunter, D. (David), Ingelsson, E. (Erik), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark I.), Mohlke, K.L. (Karen), O´Connell, J.R., Schlessinger, D. (David), Strachan, D.P. (David), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia M.), Heid, I.M. (Iris), North, K.E. (Kari), Borecki, I.B. (Ingrid), Kutalik, Z. (Zoltán), Loos, R.J.F. (Ruth), Winkler, T.W. (Thomas W.), Justice, A.E. (Anne), Graff, M.J. (Maud J.L.), Barata, L. (Llilda), Feitosa, M.F. (Mary Furlan), Chu, S. (Su), Czajkowski, J. (Jacek), Esko, T. (Tõnu), Fall, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Lu, Y. (Yingchang), Mägi, R. (Reedik), Mihailov, E. (Evelin), Pers, T.H. (Tune), Rüeger, S. (Sina), Teumer, A. (Alexander), Ehret, G.B. (Georg), Ferreira, T. (Teresa), Heard-Costa, N.L. (Nancy), Karjalainen, J. (Juha), Lagou, V. (Vasiliki), Mahajan, A. (Anubha), Neinast, M.D. (Michael D.), Prokopenko, I. (Inga), Simino, J. (Jeannette), Teslovich, T.M. (Tanya M.), Jansen, R., Westra, H.J. (Harm-Jan), White, C.C. (Charles), Absher, D. (Devin), Ahluwalia, T.S. (Tarunveer Singh), Ahmad, S. (Shafqat), Albrecht, E. (Eva), Alves, A.C. (Alexessander Couto), Bragg-Gresham, J.L. (Jennifer L.), Craen, A.J. (Anton) de, Bis, J.C. (Joshua), Bonnefond, A. (Amélie), Boucher, G. (Gabrielle), Cadby, G. (Gemma), Cheng, Y.-C. (Yu-Ching), Chiang, C.W. (Charleston W K), Delgado, G., Demirkan, A. (Ayşe), Dueker, N. (Nicole), Eklund, N. (Niina), Eiriksdottir, G. (Gudny), Eriksson, J. (Joel), Feenstra, B. (Bjarke), Fischer, K. (Krista), Frau, F. (Francesca), Galesloot, T.E. (Tessel), Geller, F. (Frank), Goel, A. (Anuj), Gorski, M. (Mathias), Grammer, T.B. (Tanja), Gustafsson, S. (Stefan), Haitjema, S. (Saskia), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Jacobs, K.B. (Kevin), Johansson, A. (Åsa), Kaakinen, M. (Marika), Kleber, M.E. (Marcus), Lahti, J. (Jari), Leach, I.M. (Irene Mateo), Lehne, B. (Benjamin), Liu, Y. (Youfang), Lo, K.S., Lorentzon, M. (Mattias), Luan, J. (Jian'An), Madden, P.A. (Pamela), Mangino, M. (Massimo), McKnight, B. (Barbara), Medina-Gomez, C. (Carolina), Monda, K.L. (Keri), Montasser, M.E. (May E.), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Panoutsopoulou, K. (Kalliope), Pascoe, L. (Laura), Paternoster, L. (Lavinia), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rizzi, F. (Federica), Rose, L.M. (Lynda), Ryan, K.A. (Kathy A.), Salo, P. (Perttu), Sanna, S. (Serena), Scharnagl, H. (Hubert), Shi, J. (Jianxin), Smith, A.V. (Albert Vernon), Southam, L. (Lorraine), Stancáková, A. (Alena), Steinthorsdottir, V. (Valgerdur), Strawbridge, R.J. (Rona), Sung, Y.J. (Yun Ju), Tachmazidou, I. (Ioanna), Tanaka, T. (Toshiko), Thorleifsson, G. (Gudmar), Trompet, S. (Stella), Pervjakova, N. (Natalia), Tyrer, J.P. (Jonathan), Vandenput, L. (Liesbeth), Van Der Laan, S.W. (Sander W.), Velde, N. (Nathalie) van der, Setten, J. (Jessica) van, Vliet-Ostaptchouk, J.V. (Jana) van, Verweij, N. (Niek), Vlachopoulou, E. (Efthymia), Waite, L. (Lindsay), Wang, S.R. (Sophie), Wang, Z. (Zhaoming), Wild, S.H. (Sarah), Willenborg, C. (Christina), Wilson, J.F. (James), Wong, A. (Andrew), Yang, J. (Jian), Yengo, L. (Loic), Yerges-Armstrong, L.M. (Laura), Yu, L. (Lei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Andersson, E.A. (Ehm Astrid), Bakker, S.J.L. (Stephan), Baldassarre, D. (Damiano), Banasik, K. (Karina), Barcella, M. (Matteo), Barlassina, C. (Cristina), Bellis, C. (Claire), Benaglio, P. (Paola), Blangero, J. (John), Blüher, M. (Matthias), Bonnet, F. (Fabrice), Bonnycastle, L.L. (Lori), Boyd, H.A. (Heather), Bruinenberg, M. (M.), Buchman, A.S. (Aron S.), Campbell, H. (Harry), Chen, Y.D. (Y.), Chines, P.S. (Peter), Claudi-Boehm, S. (Simone), Cole, J.W. (John W.), Collins, F.S. (Francis), Geus, E.J.C. (Eco) de, Groot, L.C.P.G.M. (Lisette) de, Dimitriou, M. (Maria), Duan, J. (Jubao), Enroth, S. (Stefan), Eury, E. (Elodie), Farmaki, A.-E. (Aliki-Eleni), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gejman, P.V. (Pablo), Gigante, B. (Bruna), Glorioso, N. (Nicola), Go, A.T.J.I. (Attie), Gottesman, R.F. (Rebecca), Gräßler, J. (Jürgen), Grallert, H. (Harald), Grarup, N. (Niels), Gu, Y.-M. (Yu-Mei), Broer, L. (Linda), Ham, A.C. (Annelies), Hansen, T. (T.), Harris, T.B. (Tamara), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Heath, A.C. (Andrew), Henders, A.K. (Anjali), Hernandez, D.G. (Dena), Hillege, H.L. (Hans), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Hui, J. (Jennie), Husemoen, L.L. (Lise L.), Hutri-Kähönen, N. (Nina), Hysi, P.G. (Pirro), Illig, T. (Thomas), Jager, P.L. (Philip) de, Jalilzadeh, S. (Shapour), Jorgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Juonala, M. (Markus), Kanoni, S. (Stavroula), Karaleftheri, M. (Maria), Khaw, K.T., Kinnunen, L. (Leena), Kittner, T. (Thomas), Koenig, W. (Wolfgang), Kolcic, I. (Ivana), Kovacs, P. (Peter), Krarup, N.T. (Nikolaj T.), Kratzer, W. (Wolfgang), Krüger, J. (Janine), Kuh, D. (Diana), Kumari, M. (Meena), Kyriakou, T. (Theodosios), Langenberg, C. (Claudia), Lannfelt, L. (Lars), Lanzani, C. (Chiara), Lotay, V. (Vaneet), Launer, L.J. (Lenore), Leander, K. (Karin), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y.-P. (Yan-Ping), Lobbens, S. (Stéphane), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Magnusson, P.K. (Patrik), McArdle, W.L. (Wendy), Menni, C. (Cristina), Merger, S. (Sigrun), Milani, L. (Lili), Montgomery, G.W. (Grant W.), Morris, A.P. (Andrew), Narisu, N. (Narisu), Nelis, M. (Mari), Ong, K.K. (Ken), Palotie, A. (Aarno), Perusse, L. (Louis), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Pouta, A. (Anneli), Rheinberger, M. (Myriam), Ribel-Madsen, R. (Rasmus), Richards, M. (Marcus), Rice, K.M. (Kenneth), Rice, T.K. (Treva K.), Rivolta, C. (Carlo), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Scott, W.R. (William R.), Sebert, S. 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(Bart), Kivimaki, M. (Mika), Knekt, P., Koistinen, H. (Heikki), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kuusisto, J. (Johanna), Maerz, W. (Winfried), Martin, N.G. (Nicholas), Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), Lettre, G. (Guillaume), Levinson, D.F. (Douglas), Kao, W.H.L. (Wen), Lokki, M.L., Mäntyselkä, P. (Pekka), Melbye, M. (Mads), Metspalu, A. (Andres), Mitchell, B.D. (Braxton), Moll, F.L. (Frans), Murray, J.C. (Jeffrey), Musk, A.W. (Arthur), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), Palmer, C. (Cameron), Pankow, J.S. (James), Pasterkamp, G. (Gerard), Pedersen, N.L. (Nancy), Pedersen, O. (Oluf), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce M.), Qi, L. (Lu), Quertermous, T. (Thomas), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Rioux, J.D. (John), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Saltevo, J. (Juha), Sattar, N. (Naveed), Schunkert, H. (Heribert), Schwarz, P.E.H. (Peter), Shuldiner, A.R. (Alan), Sinisalo, J. (Juha), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Staessen, J.A. (Jan A.), Stefania, B. (Bandinelli), Thorsteinsdottir, U. (Unnur), Stumvoll, M. (Michael), Tardif, J.-C. (Jean-Claude), Tremoli, E. (Elena), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Verbeek, A.L.M., Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Vitart, V. (Veronique), Völzke, H. (Henry), Vollenweider, P. (Peter), Waeber, G. (Gérard), Walker, M. (Mark), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Zeggini, E. (Eleftheria), Chakravarti, A. (Aravinda), Clegg, D.J. (Deborah J.), Cupples, L.A. (Adrienne), Gordon-Larsen, P. (Penny), Jaquish, C.E. (Cashell), Rao, D.C. (Dabeeru C.), Abecasis, G.R. (Goncalo R.), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Berndt, S.I. (Sonja), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C.S. (Caroline), Groop, L. (Leif), Hunter, D. (David), Ingelsson, E. (Erik), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark I.), Mohlke, K.L. (Karen), O´Connell, J.R., Schlessinger, D. (David), Strachan, D.P. (David), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia M.), Heid, I.M. (Iris), North, K.E. (Kari), Borecki, I.B. (Ingrid), Kutalik, Z. (Zoltán), and Loos, R.J.F. (Ruth)
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for B
Published: 2015
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39. Change in prescription pattern as a potential marker for adverse drug reactions of angiotensin converting enzyme inhibitors

Author: Mahmoudpour, S.H. (Seyed Hamidreza), Asselbergs, F.W. (Folkert), Keyser, C.E. (Catherina Elisabeth) de, Souverein, P. (Patrick), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Boer, A.C. (Anton) de, Maitland-van der Zee, A-H. (Anke-Hilse), Mahmoudpour, S.H. (Seyed Hamidreza), Asselbergs, F.W. (Folkert), Keyser, C.E. (Catherina Elisabeth) de, Souverein, P. (Patrick), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Boer, A.C. (Anton) de, and Maitland-van der Zee, A-H. (Anke-Hilse)
Abstract: Background Angiotensin converting enzyme inhibitors (ACEIs) are among the most frequently prescribed groups of medications. ACEI-induced adverse drug reactions (ADRs) are the main reason to discontinue or switch ACEI treatment. ADRs information is not available in prescription databases. Objective To identify a proxy for ACEI-induced ADRs in prescription databases. Setting The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the Netherlands and has included 14,926 subjects aged 45 years or older. Methods All ACEI starters from 2000 to 2011 were identified using prescription data within the Rotterdam Study. Participants were classified into 4 mutually exclusive groups: continuing, discontinuing, switching to angiotensin receptor blockers (ARBs), and switching to other antihypertensives. For categorization, the maximum time-interval between two prescription periods was set at 3 and 6 months. Subsequently, primary care physician files were searched and clinical events were classified as definite ADRs, probable ADRs, possible ADRs and
Published: 2015
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40. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author: Kato, N. (Norihiro), Loh, M. (Marie), Takeuchi, F. (Fumihiko), Verweij, N. (Niek), Wang, X. (Xu), Zhang, W. (Weihua), NKelly, T. (Tanika), Saleheen, D., Lehne, B. (Benjamin), Leach, I.M. (Irene Mateo), Drong, A. (Alexander), Abbott, J. (James), Wahl, S. (Simone), Tan, S.-T. (Sian-Tsung), Scott, W.R. (William R.), Campanella, G. (Gianluca), Chadeau-Hyam, M. (Marc), Afzal, U. (Uzma), Ahluwalia, T.S. (Tarunveer Singh), Bonder, M.J. (Marc), Chen, P. (Ping), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Esko, T. (Tõnu), Go, M.J. (Min Jin), Harris, S.E. (Sarah), Hartiala, J. (Jaana), Kasela, S. (Silva), Kasturiratne, A. (Anuradhani), Khor, C.C., Kleber, M.E. (Marcus), Li, H. (Huaixing), Mok, Z.Y. (Zuan Yu), Nakatochi, M. (Masahiro), Sapari, N.S. (Nur Sabrina), Saxena, R. (Richa), Stewart, A.F. (Alexandre F.), Stolk, L. (Lisette), Tabara, Y. (Yasuharu), Teh, A.L. (Ai Ling), Wu, Y. (Ying), Wu, J.-Y. (Jer-Yuarn), Zhang, Y. (Yi), Aits, I. (Imke), Da Silva Couto Alves, A. (Alexessander), Das, S. (Shikta), Dorajoo, R. (Rajkumar), CHopewell, J. (Jemma), Kim, Y.K. (Yun Kyoung), WKoivula, R. (Robert), Luan, J. (Jian'An), Lyytikäinen, L.-P. (Leo-Pekka), NNguyen, Q. (Quang), Pereira, M.A. (Mark A), Postmus, D. (Douwe), TRaitakari, O. (Olli), Scannell Bryan, M. (Molly), Scott, R.A. (Robert), Sorice, R., Tragante, V. (Vinicius), Traglia, M. (Michela), White, J. (Jon), Yamamoto, K. (Ken), Zhang, Y. (Yonghong), Adair, L.S. (Linda), Ahmed, A. (Alauddin), Akiyama, K. (Koichi), Asif, R. (Rasheed), Aung, T. (Tin), Barroso, I.E. (Inês), Bjonnes, A. (Andrew), Braun, T.R. (Timothy R.), Cai, H. (Hui), Chang, L.-C. (Li-Ching), Chen, C.-H., Cheng, C-Y. (Ching-Yu), Chong, Y.-S. (Yap-Seng), Collins, F.S. (Francis), Courtney, R. (Regina), Davies, G. (Gail), Delgado, G., Do, L.D. (Loi D.), Doevendans, P.A. (Pieter), Gansevoort, R.T. (Ron), Gao, Y. (Ying), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grewal, J. (Jagvir), Gu, D. (D.), SWander, G. (Gurpreet), Hartikainen, A.L., Hazen, S.L. (Stanley), He, J. (Jing), Heng, C.K. (Chew-Kiat), Hixso, E.J.A. (E. James Ames), Hofman, A. (Albert), Hsu, C. (Chris), Huang, W. (Wei), Husemoen, L.L.N. (Lise Lotte), Hwang, J.-Y. (Joo-Yeon), Ichihara, S. (Sahoko), Igase, M. (Michiya), Isono, M. (Masato), Justesen, J.M. (Johanne M.), Katsuya, T. (Tomohiro), GKibriya, M. (Muhammad), Kim, Y.J., Kishimoto, M. (Miyako), Koh, W.-P. (Woon-Puay), Kohara, K. (Katsuhiko), Kumari, M. (Meena), Kwek, K. (Kenneth), Lee, N.R. (Nanette), Lee, J. (Jeannette), Liao, J. (Jie), Lieb, W. (Wolfgang), Liewald, D.C.M. (David), Matsubara, T. (Tatsuaki), Matsushita, Y. (Yumi), Meitinger, T. (Thomas), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Mononen, K. (Kari), Müller-Nurasyid, M. (Martina), Nabika, T. (Toru), Nakashima, E. (Eitaro), Ng, H.K. (Hong Kiat), Nikus, K. (Kjell), Nutile, T., Ohkubo, T. (Takayoshi), Ohnaka, K. (Keizo), Parish, S. (Sarah), Paternoster, L. (Lavinia), Peng, H. (Hao), Peters, A. (Annette), TPham, S. (Son), Pinidiyapathirage, M.J. (Mohitha J.), Rahman, M. (Mahfuzar), Rakugi, H. (Hiromi), Rolandsson, O. (Olov), Rozario, M.A. (Michelle Ann), Ruggiero, D., Sala, C. (Cinzia), Sarju, R. (Ralhan), Shimokawa, K. (Kazuro), Snieder, H. (Harold), Sparsø, T. (Thomas), Spiering, W. (Wilko), Starr, J.M. (John), Stott, D.J. (David J.), OStram, D. (Daniel), Sugiyama, T. (Takao), Szymczak, S. (Silke), Tang, W.H.W. (W.H. Wilson), Tong, L. (Lin), Trompet, S. (Stella), Turjanmaa, V. (Väinö), Ueshima, H. (Hirotsugu), Uitterlinden, A.G. (André), Umemura, S. (Satoshi), Vaarasmaki, M. (Marja), Dam, R.M. (Rob Mvan), Gilst, W.H. (Wiek) van, Veldhuisen, D.J. (Dirk) van, Viikari, J. (Jorma), Waldenberger, M. (Melanie), Wang, Y. (Yiqin), Wang, A. (Aili), Wilson, R. (Rory), Wong, T.Y. (Tien Yin), Xiang, Y.-B. (Yong-Bing), Yamaguchi, S. (Shuhei), Ye, X. (Xingwang), Young, R. (Robin), Young, T.L. (Terri), Yuan, J.-M. (Jian-Min), Zhou, X. (Xueya), Asselbergs, F.W. (Folkert), Ciullo, M., Clarke, R. (Robert), Deloukas, P. (Panagiotis), Franke, A. (Andre), Paul, W.F. (W. Frank), Franks, S. (Steve), Friedlander, Y. (Yechiel), Gross, M.D. (Myron D.), Guo, Z. (Zhirong), Hansen, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Jørgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kajio, H. (Hiroshi), Kivimaki, M. (Mika), Lee, J.-Y. (Jong-Young), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Miki, T. (Tetsuro), Pedersen, O. (Oluf), Samani, N.J. (Nilesh), Sørensen, T.I.A. (Thorkild), Takayanagi, R. (Ryoichi), Toniolo, D. (Daniela), Ahsan, H. (Habibul), Allayee, H. (Hooman), Chen, Y.-T. (Yuan-Tsong), Danesh, J. (John), Deary, I.J. (Ian), Franco, O.H. (Oscar), Franke, L. (Lude), THeijman, B. (Bastiaan), Holbrook, J.D. (Joanna D.), Isaacs, A.J. (Aaron), Kim, B.-J. (Bong-Jo), Lin, X. (Xu), Liu, J. (Jianjun), März, W. (Winfried), Metspalu, A. (Andres), Mohlke, K.L. (Karen), Sangher, K., Harambir, D. (Dharambir), Shu, X.-O. (Xiao-Ou), Meurs, J.B.J. (Joyce) van, Vithana, E.N. (Eranga), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.W. (Bruce H.W.), Yokota, M. (Mitsuhiro), Zheng, W. (Wei), Zhu, D. (Dingliang), Vineis, P. (Paolo), Kyrtopoulos, S.A. (Soterios A.), Kleinjans, J.C.S. (Jos C.S.), McCarthy, M.I. (Mark), Soong, R. (Richie), Gieger, C. (Christian), Scott, J. (James), Teo, Y.Y. (Yik Ying), He, J. (Jiang), Elliott, P. (Paul), Tai, E.S. (Shyong), Harst, P. (Pim) van der, Kooner, J.S. (Jaspal S.), Chambers, J.C. (John), Kato, N. (Norihiro), Loh, M. (Marie), Takeuchi, F. (Fumihiko), Verweij, N. (Niek), Wang, X. (Xu), Zhang, W. (Weihua), NKelly, T. (Tanika), Saleheen, D., Lehne, B. (Benjamin), Leach, I.M. (Irene Mateo), Drong, A. (Alexander), Abbott, J. (James), Wahl, S. (Simone), Tan, S.-T. (Sian-Tsung), Scott, W.R. (William R.), Campanella, G. (Gianluca), Chadeau-Hyam, M. (Marc), Afzal, U. (Uzma), Ahluwalia, T.S. (Tarunveer Singh), Bonder, M.J. (Marc), Chen, P. (Ping), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Esko, T. (Tõnu), Go, M.J. (Min Jin), Harris, S.E. (Sarah), Hartiala, J. (Jaana), Kasela, S. (Silva), Kasturiratne, A. (Anuradhani), Khor, C.C., Kleber, M.E. (Marcus), Li, H. (Huaixing), Mok, Z.Y. (Zuan Yu), Nakatochi, M. (Masahiro), Sapari, N.S. (Nur Sabrina), Saxena, R. (Richa), Stewart, A.F. (Alexandre F.), Stolk, L. (Lisette), Tabara, Y. (Yasuharu), Teh, A.L. (Ai Ling), Wu, Y. (Ying), Wu, J.-Y. (Jer-Yuarn), Zhang, Y. (Yi), Aits, I. (Imke), Da Silva Couto Alves, A. (Alexessander), Das, S. (Shikta), Dorajoo, R. (Rajkumar), CHopewell, J. (Jemma), Kim, Y.K. (Yun Kyoung), WKoivula, R. (Robert), Luan, J. (Jian'An), Lyytikäinen, L.-P. (Leo-Pekka), NNguyen, Q. (Quang), Pereira, M.A. (Mark A), Postmus, D. (Douwe), TRaitakari, O. (Olli), Scannell Bryan, M. (Molly), Scott, R.A. (Robert), Sorice, R., Tragante, V. (Vinicius), Traglia, M. (Michela), White, J. (Jon), Yamamoto, K. (Ken), Zhang, Y. (Yonghong), Adair, L.S. (Linda), Ahmed, A. (Alauddin), Akiyama, K. (Koichi), Asif, R. (Rasheed), Aung, T. (Tin), Barroso, I.E. (Inês), Bjonnes, A. (Andrew), Braun, T.R. (Timothy R.), Cai, H. (Hui), Chang, L.-C. (Li-Ching), Chen, C.-H., Cheng, C-Y. (Ching-Yu), Chong, Y.-S. (Yap-Seng), Collins, F.S. (Francis), Courtney, R. (Regina), Davies, G. (Gail), Delgado, G., Do, L.D. (Loi D.), Doevendans, P.A. (Pieter), Gansevoort, R.T. (Ron), Gao, Y. (Ying), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grewal, J. (Jagvir), Gu, D. (D.), SWander, G. (Gurpreet), Hartikainen, A.L., Hazen, S.L. (Stanley), He, J. (Jing), Heng, C.K. (Chew-Kiat), Hixso, E.J.A. (E. James Ames), Hofman, A. (Albert), Hsu, C. (Chris), Huang, W. (Wei), Husemoen, L.L.N. (Lise Lotte), Hwang, J.-Y. (Joo-Yeon), Ichihara, S. (Sahoko), Igase, M. (Michiya), Isono, M. (Masato), Justesen, J.M. (Johanne M.), Katsuya, T. (Tomohiro), GKibriya, M. (Muhammad), Kim, Y.J., Kishimoto, M. (Miyako), Koh, W.-P. (Woon-Puay), Kohara, K. (Katsuhiko), Kumari, M. (Meena), Kwek, K. (Kenneth), Lee, N.R. (Nanette), Lee, J. (Jeannette), Liao, J. (Jie), Lieb, W. (Wolfgang), Liewald, D.C.M. (David), Matsubara, T. (Tatsuaki), Matsushita, Y. (Yumi), Meitinger, T. (Thomas), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Mononen, K. (Kari), Müller-Nurasyid, M. (Martina), Nabika, T. (Toru), Nakashima, E. (Eitaro), Ng, H.K. (Hong Kiat), Nikus, K. (Kjell), Nutile, T., Ohkubo, T. (Takayoshi), Ohnaka, K. (Keizo), Parish, S. (Sarah), Paternoster, L. (Lavinia), Peng, H. (Hao), Peters, A. (Annette), TPham, S. (Son), Pinidiyapathirage, M.J. (Mohitha J.), Rahman, M. (Mahfuzar), Rakugi, H. (Hiromi), Rolandsson, O. (Olov), Rozario, M.A. (Michelle Ann), Ruggiero, D., Sala, C. (Cinzia), Sarju, R. (Ralhan), Shimokawa, K. (Kazuro), Snieder, H. (Harold), Sparsø, T. (Thomas), Spiering, W. (Wilko), Starr, J.M. (John), Stott, D.J. (David J.), OStram, D. (Daniel), Sugiyama, T. (Takao), Szymczak, S. (Silke), Tang, W.H.W. (W.H. Wilson), Tong, L. (Lin), Trompet, S. (Stella), Turjanmaa, V. (Väinö), Ueshima, H. (Hirotsugu), Uitterlinden, A.G. (André), Umemura, S. (Satoshi), Vaarasmaki, M. (Marja), Dam, R.M. (Rob Mvan), Gilst, W.H. (Wiek) van, Veldhuisen, D.J. (Dirk) van, Viikari, J. (Jorma), Waldenberger, M. (Melanie), Wang, Y. (Yiqin), Wang, A. (Aili), Wilson, R. (Rory), Wong, T.Y. (Tien Yin), Xiang, Y.-B. (Yong-Bing), Yamaguchi, S. (Shuhei), Ye, X. (Xingwang), Young, R. (Robin), Young, T.L. (Terri), Yuan, J.-M. (Jian-Min), Zhou, X. (Xueya), Asselbergs, F.W. (Folkert), Ciullo, M., Clarke, R. (Robert), Deloukas, P. (Panagiotis), Franke, A. (Andre), Paul, W.F. (W. Frank), Franks, S. (Steve), Friedlander, Y. (Yechiel), Gross, M.D. (Myron D.), Guo, Z. (Zhirong), Hansen, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Jørgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kajio, H. (Hiroshi), Kivimaki, M. (Mika), Lee, J.-Y. (Jong-Young), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Miki, T. (Tetsuro), Pedersen, O. (Oluf), Samani, N.J. (Nilesh), Sørensen, T.I.A. (Thorkild), Takayanagi, R. (Ryoichi), Toniolo, D. (Daniela), Ahsan, H. (Habibul), Allayee, H. (Hooman), Chen, Y.-T. (Yuan-Tsong), Danesh, J. (John), Deary, I.J. (Ian), Franco, O.H. (Oscar), Franke, L. (Lude), THeijman, B. (Bastiaan), Holbrook, J.D. (Joanna D.), Isaacs, A.J. (Aaron), Kim, B.-J. (Bong-Jo), Lin, X. (Xu), Liu, J. (Jianjun), März, W. (Winfried), Metspalu, A. (Andres), Mohlke, K.L. (Karen), Sangher, K., Harambir, D. (Dharambir), Shu, X.-O. (Xiao-Ou), Meurs, J.B.J. (Joyce) van, Vithana, E.N. (Eranga), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.W. (Bruce H.W.), Yokota, M. (Mitsuhiro), Zheng, W. (Wei), Zhu, D. (Dingliang), Vineis, P. (Paolo), Kyrtopoulos, S.A. (Soterios A.), Kleinjans, J.C.S. (Jos C.S.), McCarthy, M.I. (Mark), Soong, R. (Richie), Gieger, C. (Christian), Scott, J. (James), Teo, Y.Y. (Yik Ying), He, J. (Jiang), Elliott, P. (Paul), Tai, E.S. (Shyong), Harst, P. (Pim) van der, Kooner, J.S. (Jaspal S.), and Chambers, J.C. (John)
Abstract: We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to 5.0 × 10 -21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10 -6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Published: 2015
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41. Directional dominance on stature and cognition in diverse human populations

Author: Joshi, P.K. (Peter), Esko, T. (Tõnu), Mattsson, H. (Hannele), Eklund, N. (Niina), Gandin, I. (Ilaria), Nutile, T., Jackson, A.U. (Anne), Schurmann, C. (Claudia), Smith, A.V. (Davey), Zhang, W. (Weihua), Okada, Y. (Yukinori), Stancáková, A. (Alena), Faul, J.D. (Jessica D.), Zhao, W. (Wei), Bartz, T.M. (Traci M.), Concas, M.P. (Maria Pina), Franceschini, N. (Nora), Enroth, S. (Stefan), Vitart, V. (Veronique), Trompet, S. (Stella), Guo, X. (Xiuqing), Chasman, D.I. (Daniel), O'Connel, J.R. (Jeffrey R.), Corre, T. (Tanguy), Nongmaithem, S.S. (Suraj S.), Chen, Y. (Yuning), Mangino, M. (Massimo), Ruggiero, D., Traglia, M. (Michela), Farmaki, A.-E. (Aliki-Eleni), Kacprowski, T. (Tim), Bjonnes, A. (Andrew), Spek, A. (Ashley) van der, Wu, Y. (Ying), Giri, A.K. (Anil K.), Yanek, L.R. (Lisa), Wang, L. (Lihua), Hofer, E. (Edith), Rietveld, C.A. (Niels), McLeod, O. (Olga), Cornelis, M. (Marilyn), Pattaro, C. (Cristian), Verweij, N. (Niek), Baumbach, C. (Clemens), Abdellaoui, A. (Abdel), Warren, H. (Helen), Vuckovic, D. (Dragana), Mei, H. (Hao), Bouchard, C. (Claude), Perry, J.R.B. (John), Cappellani, S. (Stefania), Mirza, S.S. (Saira), Benton, M.C. (Miles C.), Broeckel, U. (Ulrich), Medland, S.E. (Sarah), Lind, P.A. (Penelope), Malerba, G. (Giovanni), Drong, A. (Alexander), Yengo, L. (Loic), Bielak, L.F. (Lawrence F.), Zhi, D. (Degui), Most, P.J. (Peter) van der, Shriner, D. (Daniel), Mägi, R. (Reedik), Hemani, G., Karaderi, T. (Tugce), Wang, Z. (Zhaoming), Liu, T. (Tian), Demuth, I. (Ilja), Zhao, J.H. (Jing Hua), Meng, W. (Weihua), Lataniotis, L. (Lazaros), Van Der Laan, S.W. (Sander W.), Bradfield, J.P. (Jonathan), Wood, A.R. (Andrew), Bonnefond, A. (Amélie), Ahluwalia, T.S. (Tarunveer Singh), Hall, L.M. (Leanne M.), Salvi, E. (Erika), Yazar, S. (Seyhan), Carstensen, L. (Lisbeth), Haan, H.G. (Hugoline) de, Abney, M. (Mark), Afzal, U. (Uzma), Allison, M.A. (Matthew), Amin, N. (Najaf), Asselbergs, F.W. (Folkert W.), Bakker, S.J.L. (Stephan), Barr, R.G. (Graham), Baumeister, S.E. (Sebastian), Benjamin, D.J. (Daniel J.), Bergmann, S. (Sven), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin P.), Campbell, A. (Archie), Chakravarti, A. (Aravinda), Chan, Y. (Yingleong), Chanock, S.J. (Stephen), Chen, C. (Constance), Chen, Y.-D.I. (Y.-D. Ida), Collins, F.S. (Francis), Connell, J. (John), Correa, A. (Adolfo), Cupples, L.A. (Adrienne), Davies, G. (Gail), Dörr, M. (Marcus), Ehret, G.B. (Georg), Ellis, S.B. (Stephen B.), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Ford, I., Fox, C.S. (Caroline), Frayling, T.M. (Timothy), Friedrich, N. (Nele), Geller, F. (Frank), Scotland, G. (Generation), Gillham-Nasenya, I. (Irina), Gottesman, R.F. (Rebecca), Graff, M.J. (Maud J.L.), Grodstein, F. (Francine), Gu, C. (Charles), Haley, C. (Chris), Hammond, C.J. (Christopher), Harris, S.E. (Sarah), Harris, T.B. (Tamara), Hastie, N. (Nick), Heard-Costa, N.L. (Nancy), Heikkilä, K. (Kauko), Hocking, L.J. (Lynne), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Huffman, J.E. (Jennifer), Hysi, P.G. (Pirro), Ikram, M.A. (Arfan), Ingelsson, E. (Erik), Joensuu, A. (Anni), Johansson, A. (Åsa), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanoni, S. (Stavroula), Kerr, S.M. (Shona), Khan, N.M. (Nazir M.), Koellinger, Ph.D. (Philipp), Koistinen, H.A. (Heikki A.), Kooner, M.K. (Manraj K.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lahti, J. (Jari), Launer, L.J. (Lenore), Lea, R.A. (Rodney A.), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Lind, L. (Lars), Loh, M. (Marie), Lokki, M.L., London, S.J. (Stephanie J.), Loomis, S.J. (Stephanie J.), Loukola, A. (Anu), Lu, Y. (Yingchang), Lumley, T. (Thomas), Lundqvist, A. (Annamari), Männistö, S. (Satu), Marques-Vidal, P. (Pedro), Masciullo, C. (Corrado), Matchan, A. (Angela), Mathias, J. (Jasmine), Matsuda, K. (Koichi), Meigs, J.B. (James), Meisinger, C. (Christa), Meitinger, T. (Thomas), Menni, C. (Cristina), Mentch, F.D. (Frank), Mihailov, E. (Evelin), Milani, L. (Lili), Montasser, M.E. (May E.), Montgomery, G.W. (Grant), Morrison, A.C. (Alanna), Myers, R.H. (Richard), Nadukuru, R. (Rajiv), Navarro, P. (Pau), Nalis, M. (Mari), Nieminen, M.S. (Markku S.), Nolte, I.M. (Ilja M.), O'Connor, G.T. (George), Ogunniyi, A. (Adesola), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Pankow, J.S. (James), Patarcic, I. (Inga), Pavani, F. (Francesca), Peyser, P.A. (Patricia A.), Pietilainen, K.H. (Kirsi Hannele), Poulter, N.R. (Neil), Prokopenko, I. (Inga), Ralhan, S. (Sarju), Redmond, P. (Paul), Rich, S.S. (Stephen S.), Rissanen, H. (Harri), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rose, R.J. (Richard J.), Sala, C. (Cinzia), Salako, B. (Babatunde), Salomaa, V. (Veikko), Sarin, A.-P., Saxena, R. (Richa), Schmidt, R. (Reinhold), Scott, L.J. (Laura), Scott, W.R. (William R.), Sennblad, B. (Bengt), Seshadri, S. (Sudha), Sever, P. (Peter), Shrestha, S. (Smeeta), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Sotoodehnia, N. (Nona), Southam, L. (Lorraine), Stanton, A. (Alice), Stathopoulou, M.G. (Maria G), Strauch, K. (Konstantin), Strawbridge, R.J. (Rona), Suderman, M.J. (Matthew J.), Tandon, N. (Nikhil), Tang, S.-T. (Sian-Tsun), Taylor, K.D. (Kent D.), Tayo, B. (Bamidele), Töglhofer, A.M. (Anna Maria), Tomaszewski, M. (Maciej), Tsernikova, N. (Natalia), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vaidya, D. (Dhananjay), Hylckama Vlieg, A. (Astrid) van, Setten, J. (Jessica) van, Vasankari, T. (Tuula), Vedantam, S. (Sailaja), Vlachopoulou, E. (Efthymia), Vozzi, D. (Diego), Vuoksimaa, E. (Eero), Waldenberger, M. (Melanie), Ware, E.B. (Erin B.), Wentworth-Shields, W. (William), Whitfield, J. (John), Wild, S. (Sarah), Willemsen, G.A.H.M. (Gonneke), Yajnik, C.S. (Chittaranjan S.), Yao, J. (Jie), Zaza, G. (Gianluigi), Zhu, X. (Xiaofeng), Salem, R.M. (Rany), Melbye, M. (Mads), Bisgaard, H. (Hans), Samani, N.J. (Nilesh), Cusi, D. (Daniele), Mackey, D.A. (David A.), Cooper, R.S. (Richard S.), Froguel, P. (Philippe), Pasterkamp, G. (Gerard), Grant, S.F.A. (Struan F.A.), Hakonarson, H. (Hakon), Ferrucci, L. (Luigi), Scott, R.A. (Robert), Morris, A.D. (Andrew), Palmer, C.N.A. (Colin), Dedoussis, G.V. (George V.), Deloukas, P. (Panagiotis), Bertram, L. (Lars), Lindenberger, U. (Ulman), Berndt, S.I. (Sonja), Lindgren, C.M. (Cecilia), Timpson, N.J. (Nicholas), Tönjes, A. (Anke), Munroe, P. (Patricia), Sørensen, T.I.A. (Thorkild I.A.), Rotimi, C. (Charles), Arnett, D.K. (Donna), Oldehinkel, A.J. (Albertine), Kardia, S.L.R. (Sharon), Balkau, B. (Beverley), Gambaro, G. (Giovanni), Morris, A.P. (Andrew), Eriksson, J.G. (Johan G.), Wright, M.J. (Margaret), Martin, N.G. (Nicholas), Hunt, S.C. (Steven), Starr, J.M. (John), Deary, I.J. (Ian), Griffiths, L.R. (Lyn R.), Tiemeier, H.W. (Henning), Pirastu, N. (Nicola), Kaprio, J. (Jaakko), Wareham, N.J. (Nick), Perusse, L. (Louis), Wilson, J.G. (James), Girotto, S., Caulfield, M. (Mark), Raitakari, O.T. (Olli T.), Boomsma, D.I. (Dorret), Gieger, C. (Christian), van der Harst, P., Hicks, A.A. (Andrew), Kraft, P. (Peter), Sinisalo, J. (Juha), Knekt, P., Johannesson, M. (Magnus), Magnusson, P.K.E. (Patrik K. E.), Hamsten, A. (Anders), Borecki, I.B. (Ingrid), Vartiainen, E. (Erkki), Becker, D.M. (Diane), Bharadwaj, D. (Dwaipayan), Mohlke, K.L. (Karen), Boehnke, M. (Michael), Duijn, C.M. (Cornelia) van, Sanghera, D.K. (Dharambir), Teumer, A. (Alexander), Zeggini, E. (Eleftheria), Metspalu, A. (Andres), Gasparini, P. (Paolo), Ulivi, S. (Shelia), Ober, C. (Carole), Toniolo, D. (Daniela), Rudan, I. (Igor), Porteous, D.J. (David J.), Ciullo, M., Spector, T.D. (Timothy), Hayward, C. (Caroline), Dupuis, J. (Josée), Loos, R.J.F. (Ruth), Wright, A. (Alan), Chandak, G.R. (Giriraj), Vollenweider, P. (Peter), Shuldiner, A.R. (Alan), Ridker, P.M. (Paul), Rotter, J.I. (Jerome I.), Sattar, N. (Naveed), Gyllensten, U. (Ulf), North, K.E. (Kari), Pirastu, M. (Mario), Psaty, B.M. (Bruce), Weir, D.R. (David), Laakso, M. (Markku), Gudnason, V. (Vilmundur), Takahashi, A. (Atsushi), Chambers, J.C. (John C.), Kooner, J.S. (Jaspal S.), Strachan, D.P. (David P.), Campbell, H. (Harry), Hirschhorn, J.N. (Joel N.), Perola, M. (Markus), Polasek, O. (Ozren), Wilson, J.F. (James), Joshi, P.K. (Peter), Esko, T. (Tõnu), Mattsson, H. (Hannele), Eklund, N. (Niina), Gandin, I. (Ilaria), Nutile, T., Jackson, A.U. (Anne), Schurmann, C. (Claudia), Smith, A.V. (Davey), Zhang, W. (Weihua), Okada, Y. (Yukinori), Stancáková, A. (Alena), Faul, J.D. (Jessica D.), Zhao, W. (Wei), Bartz, T.M. (Traci M.), Concas, M.P. (Maria Pina), Franceschini, N. (Nora), Enroth, S. (Stefan), Vitart, V. (Veronique), Trompet, S. (Stella), Guo, X. (Xiuqing), Chasman, D.I. (Daniel), O'Connel, J.R. (Jeffrey R.), Corre, T. (Tanguy), Nongmaithem, S.S. (Suraj S.), Chen, Y. (Yuning), Mangino, M. (Massimo), Ruggiero, D., Traglia, M. (Michela), Farmaki, A.-E. (Aliki-Eleni), Kacprowski, T. (Tim), Bjonnes, A. (Andrew), Spek, A. (Ashley) van der, Wu, Y. (Ying), Giri, A.K. (Anil K.), Yanek, L.R. (Lisa), Wang, L. (Lihua), Hofer, E. (Edith), Rietveld, C.A. (Niels), McLeod, O. (Olga), Cornelis, M. (Marilyn), Pattaro, C. (Cristian), Verweij, N. (Niek), Baumbach, C. (Clemens), Abdellaoui, A. (Abdel), Warren, H. (Helen), Vuckovic, D. (Dragana), Mei, H. (Hao), Bouchard, C. (Claude), Perry, J.R.B. (John), Cappellani, S. (Stefania), Mirza, S.S. (Saira), Benton, M.C. (Miles C.), Broeckel, U. (Ulrich), Medland, S.E. (Sarah), Lind, P.A. (Penelope), Malerba, G. (Giovanni), Drong, A. (Alexander), Yengo, L. (Loic), Bielak, L.F. (Lawrence F.), Zhi, D. (Degui), Most, P.J. (Peter) van der, Shriner, D. (Daniel), Mägi, R. (Reedik), Hemani, G., Karaderi, T. (Tugce), Wang, Z. (Zhaoming), Liu, T. (Tian), Demuth, I. (Ilja), Zhao, J.H. (Jing Hua), Meng, W. (Weihua), Lataniotis, L. (Lazaros), Van Der Laan, S.W. (Sander W.), Bradfield, J.P. (Jonathan), Wood, A.R. (Andrew), Bonnefond, A. (Amélie), Ahluwalia, T.S. (Tarunveer Singh), Hall, L.M. (Leanne M.), Salvi, E. (Erika), Yazar, S. (Seyhan), Carstensen, L. (Lisbeth), Haan, H.G. (Hugoline) de, Abney, M. (Mark), Afzal, U. (Uzma), Allison, M.A. (Matthew), Amin, N. (Najaf), Asselbergs, F.W. (Folkert W.), Bakker, S.J.L. (Stephan), Barr, R.G. (Graham), Baumeister, S.E. (Sebastian), Benjamin, D.J. (Daniel J.), Bergmann, S. (Sven), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin P.), Campbell, A. (Archie), Chakravarti, A. (Aravinda), Chan, Y. (Yingleong), Chanock, S.J. (Stephen), Chen, C. (Constance), Chen, Y.-D.I. (Y.-D. Ida), Collins, F.S. (Francis), Connell, J. (John), Correa, A. (Adolfo), Cupples, L.A. (Adrienne), Davies, G. (Gail), Dörr, M. (Marcus), Ehret, G.B. (Georg), Ellis, S.B. (Stephen B.), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Ford, I., Fox, C.S. (Caroline), Frayling, T.M. (Timothy), Friedrich, N. (Nele), Geller, F. (Frank), Scotland, G. (Generation), Gillham-Nasenya, I. (Irina), Gottesman, R.F. (Rebecca), Graff, M.J. (Maud J.L.), Grodstein, F. (Francine), Gu, C. (Charles), Haley, C. (Chris), Hammond, C.J. (Christopher), Harris, S.E. (Sarah), Harris, T.B. (Tamara), Hastie, N. (Nick), Heard-Costa, N.L. (Nancy), Heikkilä, K. (Kauko), Hocking, L.J. (Lynne), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Huffman, J.E. (Jennifer), Hysi, P.G. (Pirro), Ikram, M.A. (Arfan), Ingelsson, E. (Erik), Joensuu, A. (Anni), Johansson, A. (Åsa), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanoni, S. (Stavroula), Kerr, S.M. (Shona), Khan, N.M. (Nazir M.), Koellinger, Ph.D. (Philipp), Koistinen, H.A. (Heikki A.), Kooner, M.K. (Manraj K.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lahti, J. (Jari), Launer, L.J. (Lenore), Lea, R.A. (Rodney A.), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Lind, L. (Lars), Loh, M. (Marie), Lokki, M.L., London, S.J. (Stephanie J.), Loomis, S.J. (Stephanie J.), Loukola, A. (Anu), Lu, Y. (Yingchang), Lumley, T. (Thomas), Lundqvist, A. (Annamari), Männistö, S. (Satu), Marques-Vidal, P. (Pedro), Masciullo, C. (Corrado), Matchan, A. (Angela), Mathias, J. (Jasmine), Matsuda, K. (Koichi), Meigs, J.B. (James), Meisinger, C. (Christa), Meitinger, T. (Thomas), Menni, C. (Cristina), Mentch, F.D. (Frank), Mihailov, E. (Evelin), Milani, L. (Lili), Montasser, M.E. (May E.), Montgomery, G.W. (Grant), Morrison, A.C. (Alanna), Myers, R.H. (Richard), Nadukuru, R. (Rajiv), Navarro, P. (Pau), Nalis, M. (Mari), Nieminen, M.S. (Markku S.), Nolte, I.M. (Ilja M.), O'Connor, G.T. (George), Ogunniyi, A. (Adesola), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Pankow, J.S. (James), Patarcic, I. (Inga), Pavani, F. (Francesca), Peyser, P.A. (Patricia A.), Pietilainen, K.H. (Kirsi Hannele), Poulter, N.R. (Neil), Prokopenko, I. (Inga), Ralhan, S. (Sarju), Redmond, P. (Paul), Rich, S.S. (Stephen S.), Rissanen, H. (Harri), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rose, R.J. (Richard J.), Sala, C. (Cinzia), Salako, B. (Babatunde), Salomaa, V. (Veikko), Sarin, A.-P., Saxena, R. (Richa), Schmidt, R. (Reinhold), Scott, L.J. (Laura), Scott, W.R. (William R.), Sennblad, B. (Bengt), Seshadri, S. (Sudha), Sever, P. (Peter), Shrestha, S. (Smeeta), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Sotoodehnia, N. (Nona), Southam, L. (Lorraine), Stanton, A. (Alice), Stathopoulou, M.G. (Maria G), Strauch, K. (Konstantin), Strawbridge, R.J. (Rona), Suderman, M.J. (Matthew J.), Tandon, N. (Nikhil), Tang, S.-T. (Sian-Tsun), Taylor, K.D. (Kent D.), Tayo, B. (Bamidele), Töglhofer, A.M. (Anna Maria), Tomaszewski, M. (Maciej), Tsernikova, N. (Natalia), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vaidya, D. (Dhananjay), Hylckama Vlieg, A. (Astrid) van, Setten, J. (Jessica) van, Vasankari, T. (Tuula), Vedantam, S. (Sailaja), Vlachopoulou, E. (Efthymia), Vozzi, D. (Diego), Vuoksimaa, E. (Eero), Waldenberger, M. (Melanie), Ware, E.B. (Erin B.), Wentworth-Shields, W. (William), Whitfield, J. (John), Wild, S. (Sarah), Willemsen, G.A.H.M. (Gonneke), Yajnik, C.S. (Chittaranjan S.), Yao, J. (Jie), Zaza, G. (Gianluigi), Zhu, X. (Xiaofeng), Salem, R.M. (Rany), Melbye, M. (Mads), Bisgaard, H. (Hans), Samani, N.J. (Nilesh), Cusi, D. (Daniele), Mackey, D.A. (David A.), Cooper, R.S. (Richard S.), Froguel, P. (Philippe), Pasterkamp, G. (Gerard), Grant, S.F.A. (Struan F.A.), Hakonarson, H. (Hakon), Ferrucci, L. (Luigi), Scott, R.A. (Robert), Morris, A.D. (Andrew), Palmer, C.N.A. (Colin), Dedoussis, G.V. (George V.), Deloukas, P. (Panagiotis), Bertram, L. (Lars), Lindenberger, U. (Ulman), Berndt, S.I. (Sonja), Lindgren, C.M. (Cecilia), Timpson, N.J. (Nicholas), Tönjes, A. (Anke), Munroe, P. (Patricia), Sørensen, T.I.A. (Thorkild I.A.), Rotimi, C. (Charles), Arnett, D.K. (Donna), Oldehinkel, A.J. (Albertine), Kardia, S.L.R. (Sharon), Balkau, B. (Beverley), Gambaro, G. (Giovanni), Morris, A.P. (Andrew), Eriksson, J.G. (Johan G.), Wright, M.J. (Margaret), Martin, N.G. (Nicholas), Hunt, S.C. (Steven), Starr, J.M. (John), Deary, I.J. (Ian), Griffiths, L.R. (Lyn R.), Tiemeier, H.W. (Henning), Pirastu, N. (Nicola), Kaprio, J. (Jaakko), Wareham, N.J. (Nick), Perusse, L. (Louis), Wilson, J.G. (James), Girotto, S., Caulfield, M. (Mark), Raitakari, O.T. (Olli T.), Boomsma, D.I. (Dorret), Gieger, C. (Christian), van der Harst, P., Hicks, A.A. (Andrew), Kraft, P. (Peter), Sinisalo, J. (Juha), Knekt, P., Johannesson, M. (Magnus), Magnusson, P.K.E. (Patrik K. E.), Hamsten, A. (Anders), Borecki, I.B. (Ingrid), Vartiainen, E. (Erkki), Becker, D.M. (Diane), Bharadwaj, D. (Dwaipayan), Mohlke, K.L. (Karen), Boehnke, M. (Michael), Duijn, C.M. (Cornelia) van, Sanghera, D.K. (Dharambir), Teumer, A. (Alexander), Zeggini, E. (Eleftheria), Metspalu, A. (Andres), Gasparini, P. (Paolo), Ulivi, S. (Shelia), Ober, C. (Carole), Toniolo, D. (Daniela), Rudan, I. (Igor), Porteous, D.J. (David J.), Ciullo, M., Spector, T.D. (Timothy), Hayward, C. (Caroline), Dupuis, J. (Josée), Loos, R.J.F. (Ruth), Wright, A. (Alan), Chandak, G.R. (Giriraj), Vollenweider, P. (Peter), Shuldiner, A.R. (Alan), Ridker, P.M. (Paul), Rotter, J.I. (Jerome I.), Sattar, N. (Naveed), Gyllensten, U. (Ulf), North, K.E. (Kari), Pirastu, M. (Mario), Psaty, B.M. (Bruce), Weir, D.R. (David), Laakso, M. (Markku), Gudnason, V. (Vilmundur), Takahashi, A. (Atsushi), Chambers, J.C. (John C.), Kooner, J.S. (Jaspal S.), Strachan, D.P. (David P.), Campbell, H. (Harry), Hirschhorn, J.N. (Joel N.), Perola, M. (Markus), Polasek, O. (Ozren), and Wilson, J.F. (James)
Abstract: Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10-300, 2.1 × 10-6, 2.5 × 10-10 and 1.8 × 10-10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been p
Published: 2015
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42. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Author: Holmes, M.V. (Michael), Dale, C.E. (Caroline), Zuccolo, L. (Luisa), Silverwood, R.J. (Richard), Guo, Y. (Yongli), Ye, Z. (Zheng), Prieto-Merino, D. (David), Dehghan, A. (Abbas), Trompet, S. (Stella), Wong, A. (Andrew), Cavadino, A. (Alana), Drogan, D. (Dagmar), Padmanabhan, S. (Sandosh), Li, S. (Shanshan), Yesupriya, A. (Ajay), Leusink, M. (Maarten), Sundstrom, J. (Johan), Hubacek, J.A. (Jaroslav A.), Pikhart, H. (Hynek), Swerdlow, D.I. (Daniel), Panayiotou, A.G. (Andrie), Borinskaya, S.A. (Svetlana), Finan, C. (Chris), Shah, S. (Sonia), Kuchenbaecker, K.B. (Karoline), Shah, T. (Tina), Engmann, J. (Jorgen), Folkersen, L. (Lasse), Eriksson, P. (Per), Ricceri, F. (Fulvio), Melander, O. (Olle), Sacerdote, C. (Carlotta), Gamble, D.M. (Dale), Rayaprolu, S. (Sruti), Ross, O.A. (Owen), McLachlan, S. (Stela), Vikhireva, O. (Olga), Sluijs, I., Scott, R.A. (Robert), Adamkova, V. (Vera), Flicker, L. (Leon), Bockxmeer, F.M. (Frank) van, Power, C. (Christine), Marques-Vidal, P. (Pedro), Meade, T. (Tom), Marmot, M. (Michael), Ferro, M.T. (María), Paulos-Pinheiro, S. (Sofia), Humphries, S.E. (Steve), Talmud, P.J., Leach, I.M. (Irene Mateo), Verweij, N. (Niek), Linneberg, A. (Allan), Skaaby, T. (Tea), Doevendans, P.A. (Pieter), Cramer, M.-J. (Maarten-Jan), Harst, P. (Pim) van der, Klungel, O.H. (Olaf), Dowling, N. (Nicole), Dominiczak, A. (Anna), Kumari, M. (Meena), Nicolaides, A.N. (Andrew), Weikert, C. (Cornelia), Boeing, H. (Heiner), Ebrahim, S. (Shanil), Gaunt, T.R. (Tom), Price, J.F. (Jackie F.), Lannfelt, L. (Lars), Peasey, A. (Anne), Kubinova, R., Pajak, A. (Andrzej), Malyutina, S., Voevoda, M.I. (Mikhail), Tamosiunas, A. (Abdonas), Maitland-van der Zee, A-H. (Anke-Hilse), Norman, P.E. (Paul), Hankey, G.J. (Graeme), Bergmann, M.M. (Manuela), Hofman, A. (Albert), Franco, O.H. (Oscar), Cooper, J. (Jim), Palmen, J. (Jutta), Spiering, W. (Wilko), Jong, P.A. (Pim) de, Kuh, D. (Diana), Hardy, R., Uitterlinden, A.G. (André), Ikram, M.A. (Arfan), Ford, I. (Ian), Hyppönen, E. (Elina), Almeida, O.P. (Osvaldo), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Hamsten, A. (Anders), Husemoen, L.L.N. (Lise Lotte), Tjønneland, A. (Anne), Tolstrup, J.S. (Janne), Rimm, E., Beulens, J.W.J. (Joline), Verschuren, W.M.M. (W. M. Monique), Onland-Moret, N.C. (Charlotte), Hofker, M.A. (Marten), Wannamethee, S.G. (Goya), Whincup, P.H. (Peter), Morris, R.W. (Richard), Vicente, A.M. (Astrid), Watkins, H. (Hugh), Farrall, M. (Martin), Jukema, J.W. (Jan Wouter), Meschia, J.F. (James F.), Cupples, L.A. (Adrienne), Sharp, S.J. (Stephen), Fornage, M. (Myriam), Kooperberg, C. (Charles), LaCroix, A.Z. (Andrea), Dai, J.Y. (James), Lanktree, M.B. (Matthew), Siscovick, D.S. (David), Jorgenson, E. (Eric), Spring, B. (Bonnie), Coresh, J. (Josef), Li, Y.R. (Yun), Buxbaum, S.G. (Sarah), Schreiner, P.J. (Pamela), Ellison, D.H. (David), Tsai, M.Y. (Michael), Patel, S.R. (Sanjay), Redline, S. (Susan), Johnson, A.D. (Andrew), Hoogeveen, R.C. (Ron), Hakonarson, H. (Hakon), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Bakker, P.I.W. (Paul) de, Kivimaki, M. (Mika), Asselbergs, F.W. (Folkert), Sattar, N. (Naveed), Lawlor, D.A. (Debbie), Whittaker, J. (John), Smith, A.V. (Davey), Mukamal, K. (Kenneth), Psaty, B.M. (Bruce), Wilson, J.G. (James), Lange, L.A. (Leslie), Hamidovic, A. (Ajna), Nordestgaard, B.G. (Børge), Bobak, M. (Martin), Leon, D.A. (David), Langenberg, C. (Claudia), Palmer, T.M. (Tom), Reiner, A.P. (Alex), Keating, J. (John), Dudbridge, F. (Frank), Casas, J.P. (Juan), Holmes, M.V. (Michael), Dale, C.E. (Caroline), Zuccolo, L. (Luisa), Silverwood, R.J. (Richard), Guo, Y. (Yongli), Ye, Z. (Zheng), Prieto-Merino, D. (David), Dehghan, A. (Abbas), Trompet, S. (Stella), Wong, A. (Andrew), Cavadino, A. (Alana), Drogan, D. (Dagmar), Padmanabhan, S. (Sandosh), Li, S. (Shanshan), Yesupriya, A. (Ajay), Leusink, M. (Maarten), Sundstrom, J. (Johan), Hubacek, J.A. (Jaroslav A.), Pikhart, H. (Hynek), Swerdlow, D.I. (Daniel), Panayiotou, A.G. (Andrie), Borinskaya, S.A. (Svetlana), Finan, C. (Chris), Shah, S. (Sonia), Kuchenbaecker, K.B. (Karoline), Shah, T. (Tina), Engmann, J. (Jorgen), Folkersen, L. (Lasse), Eriksson, P. (Per), Ricceri, F. (Fulvio), Melander, O. (Olle), Sacerdote, C. (Carlotta), Gamble, D.M. (Dale), Rayaprolu, S. (Sruti), Ross, O.A. (Owen), McLachlan, S. (Stela), Vikhireva, O. (Olga), Sluijs, I., Scott, R.A. (Robert), Adamkova, V. (Vera), Flicker, L. (Leon), Bockxmeer, F.M. (Frank) van, Power, C. (Christine), Marques-Vidal, P. (Pedro), Meade, T. (Tom), Marmot, M. (Michael), Ferro, M.T. (María), Paulos-Pinheiro, S. (Sofia), Humphries, S.E. (Steve), Talmud, P.J., Leach, I.M. (Irene Mateo), Verweij, N. (Niek), Linneberg, A. (Allan), Skaaby, T. (Tea), Doevendans, P.A. (Pieter), Cramer, M.-J. (Maarten-Jan), Harst, P. (Pim) van der, Klungel, O.H. (Olaf), Dowling, N. (Nicole), Dominiczak, A. (Anna), Kumari, M. (Meena), Nicolaides, A.N. (Andrew), Weikert, C. (Cornelia), Boeing, H. (Heiner), Ebrahim, S. (Shanil), Gaunt, T.R. (Tom), Price, J.F. (Jackie F.), Lannfelt, L. (Lars), Peasey, A. (Anne), Kubinova, R., Pajak, A. (Andrzej), Malyutina, S., Voevoda, M.I. (Mikhail), Tamosiunas, A. (Abdonas), Maitland-van der Zee, A-H. (Anke-Hilse), Norman, P.E. (Paul), Hankey, G.J. (Graeme), Bergmann, M.M. (Manuela), Hofman, A. (Albert), Franco, O.H. (Oscar), Cooper, J. (Jim), Palmen, J. (Jutta), Spiering, W. (Wilko), Jong, P.A. (Pim) de, Kuh, D. (Diana), Hardy, R., Uitterlinden, A.G. (André), Ikram, M.A. (Arfan), Ford, I. (Ian), Hyppönen, E. (Elina), Almeida, O.P. (Osvaldo), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Hamsten, A. (Anders), Husemoen, L.L.N. (Lise Lotte), Tjønneland, A. (Anne), Tolstrup, J.S. (Janne), Rimm, E., Beulens, J.W.J. (Joline), Verschuren, W.M.M. (W. M. Monique), Onland-Moret, N.C. (Charlotte), Hofker, M.A. (Marten), Wannamethee, S.G. (Goya), Whincup, P.H. (Peter), Morris, R.W. (Richard), Vicente, A.M. (Astrid), Watkins, H. (Hugh), Farrall, M. (Martin), Jukema, J.W. (Jan Wouter), Meschia, J.F. (James F.), Cupples, L.A. (Adrienne), Sharp, S.J. (Stephen), Fornage, M. (Myriam), Kooperberg, C. (Charles), LaCroix, A.Z. (Andrea), Dai, J.Y. (James), Lanktree, M.B. (Matthew), Siscovick, D.S. (David), Jorgenson, E. (Eric), Spring, B. (Bonnie), Coresh, J. (Josef), Li, Y.R. (Yun), Buxbaum, S.G. (Sarah), Schreiner, P.J. (Pamela), Ellison, D.H. (David), Tsai, M.Y. (Michael), Patel, S.R. (Sanjay), Redline, S. (Susan), Johnson, A.D. (Andrew), Hoogeveen, R.C. (Ron), Hakonarson, H. (Hakon), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Bakker, P.I.W. (Paul) de, Kivimaki, M. (Mika), Asselbergs, F.W. (Folkert), Sattar, N. (Naveed), Lawlor, D.A. (Debbie), Whittaker, J. (John), Smith, A.V. (Davey), Mukamal, K. (Kenneth), Psaty, B.M. (Bruce), Wilson, J.G. (James), Lange, L.A. (Leslie), Hamidovic, A. (Ajna), Nordestgaard, B.G. (Børge), Bobak, M. (Martin), Leon, D.A. (David), Langenberg, C. (Claudia), Palmer, T.M. (Tom), Reiner, A.P. (Alex), Keating, J. (John), Dudbridge, F. (Frank), and Casas, J.P. (Juan)
Published: 2014
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43. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author: Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), Keating, J. (John), Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), and Keating, J. (John)
Abstract: Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
Published: 2014
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44. Annotation of loci from genome-wide association studies using tissue-specifc quantitative interaction proteomics

Author: Lundby, A. (Alicia), Rossin, E. (Elizabeth), Steffensen, K.R. (Knut ), Acha, M.R. (Moshe Rav), Newton-Cheh, C. (Christopher), Pfeufer, A. (Arne), Lynch, S.N. (Stacey), Olesen, S.-P. (Søren-Peter), Brunak, S. (S.), Ellinor, P.T. (Patrick), Jukema, J.W. (Jan Wouter), Trompet, S. (Stella), Ford, I. (Ian), MacFarlane, P.W. (Peter), Krijthe, B.P. (Bouwe), Hofman, A. (Albert), Uitterlinden, A.G. (André), Stricker, B.H.Ch. (Bruno), Nathoe, H.M. (Hendrik), Spiering, W. (Wilko), Daly, M.J. (Mark), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Milan, D.J. (David), Bakker, P.I.W. (Paul) de, Lage, P. (Pedro), Olsen, J.V. (Jesper), Lundby, A. (Alicia), Rossin, E. (Elizabeth), Steffensen, K.R. (Knut ), Acha, M.R. (Moshe Rav), Newton-Cheh, C. (Christopher), Pfeufer, A. (Arne), Lynch, S.N. (Stacey), Olesen, S.-P. (Søren-Peter), Brunak, S. (S.), Ellinor, P.T. (Patrick), Jukema, J.W. (Jan Wouter), Trompet, S. (Stella), Ford, I. (Ian), MacFarlane, P.W. (Peter), Krijthe, B.P. (Bouwe), Hofman, A. (Albert), Uitterlinden, A.G. (André), Stricker, B.H.Ch. (Bruno), Nathoe, H.M. (Hendrik), Spiering, W. (Wilko), Daly, M.J. (Mark), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Milan, D.J. (David), Bakker, P.I.W. (Paul) de, Lage, P. (Pedro), and Olsen, J.V. (Jesper)
Abstract: Genome-wide association studies (GWAs) have identifed thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specifc quantitative interaction proteomics to map a network of fve genes involved in the mendelian disorder long Qt syndrome (lQts). We integrated the lQts network with GWAs loci from the corresponding common complex trait, Qt-interval variation, to identify candidate genes that were subsequently confrmed in Xenopus laevis oocytes and zebrafsh. We used the lQts protein network to flter weak GWAs signals by identifying single-nucleotide polymorphisms (snPs) in proximity to genes in the network supported by strong proteomic evidence. three snPs passing this flter reached genome-wide signifcance after replication genotyping. overall, we present a general strategy to propose candidates in GWAs loci for functional studies and to systematically flter subtle association signals using tissue-specifc quantitative interaction proteomics.
Published: 2014
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45. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author: Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, Newton-Cheh, C. (Christopher), Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, and Newton-Cheh, C. (Christopher)
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Published: 2014
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46. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author: Berndt, S.I. (Sonja), Gustafsson, S. (Stefan), Mägi, R. (Reedik), Ganna, A. (Andrea), Wheeler, E. (Eleanor), Feitosa, M.F. (Mary Furlan), Justice, A.E. (Anne), Monda, K.L. (Keri), Croteau-Chonka, D.C. (Damien), Day, F.R. (Felix), Esko, T. (Tõnu), Fall, M. (Magnus), Ferreira, T. (Teresa), Gentilini, D. (Davide), Jackson, A.U. (Anne), Luan, J., Randall, J.C. (Joshua), Vedantam, S. (Sailaja), Willer, C.J. (Cristen), Winkler, T.W. (Thomas), Wood, A.R. (Andrew), Workalemahu, T. (Tsegaselassie), Hu, Y.-J. (Yi-Juan), Lee, S.H. (Sang Hong), Liang, L. (Liming), Lin, D.Y. (Dan), Min, J. (Josine), Neale, B.M. (Benjamin), Thorleifsson, G. (Gudmar), Yang, J. (Jian), Albrecht, E. (Eva), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Cadby, G. (Gemma), Heijer, M. (Martin) den, Eklund, N. (Niina), Fischer, K. (Krista), Goel, A. (Anuj), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jarick, I. (Ivonne), Johansson, A. (Åsa), Johnson, T. (Toby), Kanoni, S. (Stavroula), Kleber, M.E. (Marcus), König, I.R. (Inke), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lamina, C. (Claudia), Lecoeur, C. (Cécile), Li, G. (Guo), Mangino, M. (Massimo), McArdle, W.L. (Wendy), Medina-Gomez, M.C. (Carolina), Müller-Nurasyid, M. (Martina), Ngwa, J.S., Nolte, I.M. (Ilja), Paternoster, L. (Lavinia), Pechlivanis, S. (Sonali), Perola, M. (Markus), Peters, M.J. (Marjolein), Preuss, M. (Michael), Rose, L.M. (Lynda), Shi, J. (Jianxin), Shungin, D. (Dmitry), Smith, A.V. (Davey), Strawbridge, R.J. (Rona), Surakka, I. (Ida), Teumer, A. (Alexander), Trip, M.D. (Mieke), Tyrer, J.P. (Jonathan), Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Waite, L. (Lindsay), Zhao, J.H. (Jing Hua), Absher, D. (Devin), Asselbergs, F.W. (Folkert), Atalay, M. (Mustafa), Attwood, A.P. (Antony), Balmforth, A.J. (Anthony), Basart, D.C.G. (Dick), Beilby, J.P. (John), Bonnycastle, L.L. (Lori), Brambilla, P. (Paolo), Bruinenberg, M. (M.), Campbell, H. (Harry), Chasman, D.I. (Daniel), Chines, P.S. (Peter), Collins, F.S. (Francis), Connell, J. (John), Cookson, W.O. (William), Faire, U. (Ulf) de, Vegt, F. (Femmie) de, Dei, M. (Mariano), Dimitriou, M. (Maria), Edkins, T. (Ted), Estrada Gil, K. (Karol), Evans, D.M. (David), Farrall, M. (Martin), Ferrario, F. (Franco), Ferrières, J. (Jean), Franke, L. (Lude), Frau, F. (Francesca), Gejman, P.V. (Pablo), Grallert, H. (Harald), Grönberg, H. (Henrik), Gudnason, V. (Vilmundur), Hall, A. (Anne), Hall, A.S. (Alistair), Hartikainen, A.L., Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Heath, A.C. (Andrew), Hebebrand, J. (Johannes), Homuth, G. (Georg), Hu, F.B. (Frank), Hunt, S.E. (Sarah), Hyppönen, E. (Elina), Iribarren, C. (Carlos), Jacobs, K.B. (Kevin), Jansson, J.-O. (John-Olov), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Kee, F. (F.), Khaw, K-T. (Kay-Tee), Kivimaki, M. (Mika), Koenig, W. (Wolfgang), Kraja, A. (Aldi), Kumari, M. (Meena), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Laitinen, J. (Jaana), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lind, L. (Lars), Lindstrom, J. (Jaana), Liu, J. (Jianjun), Liuzzi, A. (Antonio), Lokki, M.L., Lorentzon, M. (Mattias), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Manunta, P. (Paolo), Marek, D. (Diana), März, W. (Winfried), Leach, I.M. (Irene Mateo), McKnight, B. (Barbara), Medland, S.E. (Sarah), Mihailov, E. (Evelin), Milani, L. (Lili), Montgomery, G.W. (Grant), Mooser, V. (Vincent), Mühleisen, T.W. (Thomas), Munroe, P. (Patricia), Musk, A.W. (Arthur), Narisu, N. (Narisu), Navis, G. (Gerjan), Nicholson, G. (Ggeorge), Nohr, C. (Christian), Ong, K. (Ken), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Palotie, A. (Aarno), Peden, J. (John), Pedersen, N.L. (Nancy), Peters, A. (Annette), Polasek, O. (Ozren), Pouta, A. (Anneli), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Pütter, C. (Carolin), Radhakrishnan, A. (Aparna), Raitakari, O. (Olli), Rendon, A. (Augusto), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Saaristo, T. (Timo), Sambrook, J.G. (Jennifer), Sanders, A.R. (Alan), Sanna, S. (Serena), Saramies, J. (Jouko), Schipf, S. (Sabine), Schreiber, S. (Stefan), Schunkert, H. (Heribert), Shin, S.-Y., Signorini, S. (Stefano), Sinisalo, J. (Juha), Skrobek, B. (Boris), Soranzo, N. (Nicole), Stancáková, A. (Alena), Stark, K. (Klaus), Stephens, J. (Jonathan), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Stumvoll, M. (Michael), Swift, A.J. (Amy), Theodoraki, E.V. (Eirini), Thorand, B. (Barbara), Tregouet, D.-A. (David-Alexandre), Tremoli, E. (Elena), Klauw, M.M. (Melanie) van der, Meurs, J.B.J. (Joyce) van, Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Waeber, G. (Gérard), Wang, Z. (Zhaoming), Widen, E. (Elisabeth), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Winkelmann, B., Witteman, J.C.M. (Jacqueline), Wolffenbuttel, B.H.R. (Bruce), Wong, A. (Andrew), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Amouyel, P. (Philippe), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Caulfield, M. (Mark), Chanock, S.J. (Stephen), Cupples, L.A. (Adrienne), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Eriksson, J.G. (Johan), Franks, P.W. (Paul), Froguel, P. (Philippe), Gieger, C. (Christian), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hengstenberg, C. (Christian), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hinney, A. (Anke), Hofman, A. (Albert), Hovingh, G.K. (Kees), Hveem, K. (Kristian), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Jöckel, K.-H. (Karl-Heinz), Keinanen-Kiukaanniemi, S. (Sirkka), Kiemeney, L.A.L.M. (Bart), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Levinson, D.F. (Douglas), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Morris, A.D. (Andrew), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Ouwehand, W.H. (Willem), Palmer, C. (Cameron), Penninx, B.W.J.H. (Brenda), Power, C. (Christopher), Province, M.A. (Mike), Psaty, B.M. (Bruce), Qi, L. (Lu), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Snieder, H. (Harold), Sorensen, H.G., Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Tönjes, A. (Anke), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Harst, P. (Pim) van der, Vollenweider, P. (Peter), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wichmann, H.E. (Heinz Erich), Wilson, J.F. (James F), Abecasis, G.R. (Gonçalo), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Fox, C. (Craig), Frayling, T.M. (Timothy), Groop, L. (Leif), Haritunian, T. (Talin), Heid, I.M. (Iris), Hunter, D. (David), Kaplan, R.C. (Robert), Karpe, F. (Fredrik), Moffatt, M.F. (Miriam), Mohlke, K.L. (Karen), O´Connell, J.R., Pawitan, Y. (Yudi), Schadt, E.E. (Eric), Schlessinger, D. (David), Steinthorsdottir, V. (Valgerdur), Strachan, D.P. (David), Thorsteinsdottir, U. (Unnur), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Di Blasio, A.M. (Anna Maria), Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia), Meyre, D. (David), Scherag, A. (Andre), McCarthy, M.I. (Mark), Speliotes, E.K. (Elizabeth), North, K.E. (Kari), Loos, R.J.F. (Ruth), Ingelsson, E. (Erik), Berndt, S.I. (Sonja), Gustafsson, S. (Stefan), Mägi, R. (Reedik), Ganna, A. (Andrea), Wheeler, E. (Eleanor), Feitosa, M.F. (Mary Furlan), Justice, A.E. (Anne), Monda, K.L. (Keri), Croteau-Chonka, D.C. (Damien), Day, F.R. (Felix), Esko, T. (Tõnu), Fall, M. (Magnus), Ferreira, T. (Teresa), Gentilini, D. (Davide), Jackson, A.U. (Anne), Luan, J., Randall, J.C. (Joshua), Vedantam, S. (Sailaja), Willer, C.J. (Cristen), Winkler, T.W. (Thomas), Wood, A.R. (Andrew), Workalemahu, T. (Tsegaselassie), Hu, Y.-J. (Yi-Juan), Lee, S.H. (Sang Hong), Liang, L. (Liming), Lin, D.Y. (Dan), Min, J. (Josine), Neale, B.M. (Benjamin), Thorleifsson, G. (Gudmar), Yang, J. (Jian), Albrecht, E. (Eva), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Cadby, G. (Gemma), Heijer, M. (Martin) den, Eklund, N. (Niina), Fischer, K. (Krista), Goel, A. (Anuj), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jarick, I. (Ivonne), Johansson, A. (Åsa), Johnson, T. (Toby), Kanoni, S. (Stavroula), Kleber, M.E. (Marcus), König, I.R. (Inke), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lamina, C. (Claudia), Lecoeur, C. (Cécile), Li, G. (Guo), Mangino, M. (Massimo), McArdle, W.L. (Wendy), Medina-Gomez, M.C. (Carolina), Müller-Nurasyid, M. (Martina), Ngwa, J.S., Nolte, I.M. (Ilja), Paternoster, L. (Lavinia), Pechlivanis, S. (Sonali), Perola, M. (Markus), Peters, M.J. (Marjolein), Preuss, M. (Michael), Rose, L.M. (Lynda), Shi, J. (Jianxin), Shungin, D. (Dmitry), Smith, A.V. (Davey), Strawbridge, R.J. (Rona), Surakka, I. (Ida), Teumer, A. (Alexander), Trip, M.D. (Mieke), Tyrer, J.P. (Jonathan), Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Waite, L. (Lindsay), Zhao, J.H. (Jing Hua), Absher, D. (Devin), Asselbergs, F.W. (Folkert), Atalay, M. (Mustafa), Attwood, A.P. (Antony), Balmforth, A.J. (Anthony), Basart, D.C.G. (Dick), Beilby, J.P. (John), Bonnycastle, L.L. (Lori), Brambilla, P. (Paolo), Bruinenberg, M. (M.), Campbell, H. (Harry), Chasman, D.I. (Daniel), Chines, P.S. (Peter), Collins, F.S. (Francis), Connell, J. (John), Cookson, W.O. (William), Faire, U. (Ulf) de, Vegt, F. (Femmie) de, Dei, M. (Mariano), Dimitriou, M. (Maria), Edkins, T. (Ted), Estrada Gil, K. (Karol), Evans, D.M. (David), Farrall, M. (Martin), Ferrario, F. (Franco), Ferrières, J. (Jean), Franke, L. (Lude), Frau, F. (Francesca), Gejman, P.V. (Pablo), Grallert, H. (Harald), Grönberg, H. (Henrik), Gudnason, V. (Vilmundur), Hall, A. (Anne), Hall, A.S. (Alistair), Hartikainen, A.L., Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Heath, A.C. (Andrew), Hebebrand, J. (Johannes), Homuth, G. (Georg), Hu, F.B. (Frank), Hunt, S.E. (Sarah), Hyppönen, E. (Elina), Iribarren, C. (Carlos), Jacobs, K.B. (Kevin), Jansson, J.-O. (John-Olov), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Kee, F. (F.), Khaw, K-T. (Kay-Tee), Kivimaki, M. (Mika), Koenig, W. (Wolfgang), Kraja, A. (Aldi), Kumari, M. (Meena), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Laitinen, J. (Jaana), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lind, L. (Lars), Lindstrom, J. (Jaana), Liu, J. (Jianjun), Liuzzi, A. (Antonio), Lokki, M.L., Lorentzon, M. (Mattias), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Manunta, P. (Paolo), Marek, D. (Diana), März, W. (Winfried), Leach, I.M. (Irene Mateo), McKnight, B. (Barbara), Medland, S.E. (Sarah), Mihailov, E. (Evelin), Milani, L. (Lili), Montgomery, G.W. (Grant), Mooser, V. (Vincent), Mühleisen, T.W. (Thomas), Munroe, P. (Patricia), Musk, A.W. (Arthur), Narisu, N. (Narisu), Navis, G. (Gerjan), Nicholson, G. (Ggeorge), Nohr, C. (Christian), Ong, K. (Ken), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Palotie, A. (Aarno), Peden, J. (John), Pedersen, N.L. (Nancy), Peters, A. (Annette), Polasek, O. (Ozren), Pouta, A. (Anneli), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Pütter, C. (Carolin), Radhakrishnan, A. (Aparna), Raitakari, O. (Olli), Rendon, A. (Augusto), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Saaristo, T. (Timo), Sambrook, J.G. (Jennifer), Sanders, A.R. (Alan), Sanna, S. (Serena), Saramies, J. (Jouko), Schipf, S. (Sabine), Schreiber, S. (Stefan), Schunkert, H. (Heribert), Shin, S.-Y., Signorini, S. (Stefano), Sinisalo, J. (Juha), Skrobek, B. (Boris), Soranzo, N. (Nicole), Stancáková, A. (Alena), Stark, K. (Klaus), Stephens, J. (Jonathan), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Stumvoll, M. (Michael), Swift, A.J. (Amy), Theodoraki, E.V. (Eirini), Thorand, B. (Barbara), Tregouet, D.-A. (David-Alexandre), Tremoli, E. (Elena), Klauw, M.M. (Melanie) van der, Meurs, J.B.J. (Joyce) van, Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Waeber, G. (Gérard), Wang, Z. (Zhaoming), Widen, E. (Elisabeth), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Winkelmann, B., Witteman, J.C.M. (Jacqueline), Wolffenbuttel, B.H.R. (Bruce), Wong, A. (Andrew), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Amouyel, P. (Philippe), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Caulfield, M. (Mark), Chanock, S.J. (Stephen), Cupples, L.A. (Adrienne), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Eriksson, J.G. (Johan), Franks, P.W. (Paul), Froguel, P. (Philippe), Gieger, C. (Christian), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hengstenberg, C. (Christian), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hinney, A. (Anke), Hofman, A. (Albert), Hovingh, G.K. (Kees), Hveem, K. (Kristian), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Jöckel, K.-H. (Karl-Heinz), Keinanen-Kiukaanniemi, S. (Sirkka), Kiemeney, L.A.L.M. (Bart), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Levinson, D.F. (Douglas), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Morris, A.D. (Andrew), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Ouwehand, W.H. (Willem), Palmer, C. (Cameron), Penninx, B.W.J.H. (Brenda), Power, C. (Christopher), Province, M.A. (Mike), Psaty, B.M. (Bruce), Qi, L. (Lu), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Snieder, H. (Harold), Sorensen, H.G., Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Tönjes, A. (Anke), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Harst, P. (Pim) van der, Vollenweider, P. (Peter), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wichmann, H.E. (Heinz Erich), Wilson, J.F. (James F), Abecasis, G.R. (Gonçalo), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Fox, C. (Craig), Frayling, T.M. (Timothy), Groop, L. (Leif), Haritunian, T. (Talin), Heid, I.M. (Iris), Hunter, D. (David), Kaplan, R.C. (Robert), Karpe, F. (Fredrik), Moffatt, M.F. (Miriam), Mohlke, K.L. (Karen), O´Connell, J.R., Pawitan, Y. (Yudi), Schadt, E.E. (Eric), Schlessinger, D. (David), Steinthorsdottir, V. (Valgerdur), Strachan, D.P. (David), Thorsteinsdottir, U. (Unnur), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Di Blasio, A.M. (Anna Maria), Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia), Meyre, D. (David), Scherag, A. (Andre), McCarthy, M.I. (Mark), Speliotes, E.K. (Elizabeth), North, K.E. (Kari), Loos, R.J.F. (Ruth), and Ingelsson, E. (Erik)
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Published: 2013
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47. Interleukin-6 receptor pathways in abdominal aortic aneurysm

Author: Harrison, S.C. (Seamus), Smith, A.J. (Andrew), Jones, G.T. (Gregory), Swerdlow, D.I. (Daniel), Rampuri, R. (Riaz), Bown, N., Folkersen, L. (Lasse), Baas, A.F. (Annette), Borst, G.J. (Gert) de, Blankensteijn, J.D. (Jan), Price, J.F. (Jackie F.), Graaf, Y. (Yolanda) van der, McLachlan, S. (Stela), Agu, O. (Obi), Hofman, A. (Albert), Uitterlinden, A.G. (André), Franco-Cereceda, A. (Anders), Ruigrok, Y.M. (Ynte), Van'T Hof, F.N. (F.), Powell, J.T. (Janet), Rij, A.M. (Andre) van, Casas, J.P. (Juan), Eriksson, P. (Per), Holmes, M.V. (Michael), Asselbergs, F.W. (Folkert), Hingorani, A. (Aroon), Humphries, S.E. (Steve), Harrison, S.C. (Seamus), Smith, A.J. (Andrew), Jones, G.T. (Gregory), Swerdlow, D.I. (Daniel), Rampuri, R. (Riaz), Bown, N., Folkersen, L. (Lasse), Baas, A.F. (Annette), Borst, G.J. (Gert) de, Blankensteijn, J.D. (Jan), Price, J.F. (Jackie F.), Graaf, Y. (Yolanda) van der, McLachlan, S. (Stela), Agu, O. (Obi), Hofman, A. (Albert), Uitterlinden, A.G. (André), Franco-Cereceda, A. (Anders), Ruigrok, Y.M. (Ynte), Van'T Hof, F.N. (F.), Powell, J.T. (Janet), Rij, A.M. (Andre) van, Casas, J.P. (Juan), Eriksson, P. (Per), Holmes, M.V. (Michael), Asselbergs, F.W. (Folkert), Hingorani, A. (Aroon), and Humphries, S.E. (Steve)
Abstract: MethodsWe conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo.Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach.ResultsUp to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I2 = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I2 = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers.Conclusi
Published: 2013
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48. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author: Berndt, S.I. (Sonja), Gustafsson, S. (Stefan), Mägi, R. (Reedik), Ganna, A. (Andrea), Wheeler, E. (Eleanor), Feitosa, M.F. (Mary Furlan), Justice, A.E. (Anne), Monda, K.L. (Keri), Croteau-Chonka, D.C. (Damien), Day, F.R. (Felix), Esko, T. (Tõnu), Fall, M. (Magnus), Ferreira, T. (Teresa), Gentilini, D. (Davide), Jackson, A.U. (Anne), Luan, J., Randall, J.C. (Joshua), Vedantam, S. (Sailaja), Willer, C.J. (Cristen), Winkler, T.W. (Thomas), Wood, A.R. (Andrew), Workalemahu, T. (Tsegaselassie), Hu, Y.-J. (Yi-Juan), Lee, S.H. (Sang Hong), Liang, L. (Liming), Lin, D.Y. (Dan), Min, J. (Josine), Neale, B.M. (Benjamin), Thorleifsson, G. (Gudmar), Yang, J. (Jian), Albrecht, E. (Eva), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Cadby, G. (Gemma), Heijer, M. (Martin) den, Eklund, N. (Niina), Fischer, K. (Krista), Goel, A. (Anuj), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jarick, I. (Ivonne), Johansson, A. (Åsa), Johnson, T. (Toby), Kanoni, S. (Stavroula), Kleber, M.E. (Marcus), König, I.R. (Inke), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lamina, C. (Claudia), Lecoeur, C. (Cécile), Li, G. (Guo), Mangino, M. (Massimo), McArdle, W.L. (Wendy), Medina-Gomez, M.C. (Carolina), Müller-Nurasyid, M. (Martina), Ngwa, J.S., Nolte, I.M. (Ilja), Paternoster, L. (Lavinia), Pechlivanis, S. (Sonali), Perola, M. (Markus), Peters, M.J. (Marjolein), Preuss, M. (Michael), Rose, L.M. (Lynda), Shi, J. (Jianxin), Shungin, D. (Dmitry), Smith, A.V. (Davey), Strawbridge, R.J. (Rona), Surakka, I. (Ida), Teumer, A. (Alexander), Trip, M.D. (Mieke), Tyrer, J.P. (Jonathan), Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Waite, L. (Lindsay), Zhao, J.H. (Jing Hua), Absher, D. (Devin), Asselbergs, F.W. (Folkert), Atalay, M. (Mustafa), Attwood, A.P. (Antony), Balmforth, A.J. (Anthony), Basart, D.C.G. (Dick), Beilby, J.P. (John), Bonnycastle, L.L. (Lori), Brambilla, P. (Paolo), Bruinenberg, M. (M.), Campbell, H. (Harry), Chasman, D.I. (Daniel), Chines, P.S. (Peter), Collins, F.S. (Francis), Connell, J. (John), Cookson, W.O. (William), Faire, U. (Ulf) de, Vegt, F. (Femmie) de, Dei, M. (Mariano), Dimitriou, M. (Maria), Edkins, T. (Ted), Estrada Gil, K. (Karol), Evans, D.M. (David), Farrall, M. (Martin), Ferrario, F. (Franco), Ferrières, J. (Jean), Franke, L. (Lude), Frau, F. (Francesca), Gejman, P.V. (Pablo), Grallert, H. (Harald), Grönberg, H. (Henrik), Gudnason, V. (Vilmundur), Hall, A. (Anne), Hall, A.S. (Alistair), Hartikainen, A.L., Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Heath, A.C. (Andrew), Hebebrand, J. (Johannes), Homuth, G. (Georg), Hu, F.B. (Frank), Hunt, S.E. (Sarah), Hyppönen, E. (Elina), Iribarren, C. (Carlos), Jacobs, K.B. (Kevin), Jansson, J.-O. (John-Olov), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Kee, F. (F.), Khaw, K-T. (Kay-Tee), Kivimaki, M. (Mika), Koenig, W. (Wolfgang), Kraja, A. (Aldi), Kumari, M. (Meena), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Laitinen, J. (Jaana), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lind, L. (Lars), Lindstrom, J. (Jaana), Liu, J. (Jianjun), Liuzzi, A. (Antonio), Lokki, M.L., Lorentzon, M. (Mattias), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Manunta, P. (Paolo), Marek, D. (Diana), März, W. (Winfried), Leach, I.M. (Irene Mateo), McKnight, B. (Barbara), Medland, S.E. (Sarah), Mihailov, E. (Evelin), Milani, L. (Lili), Montgomery, G.W. (Grant), Mooser, V. (Vincent), Mühleisen, T.W. (Thomas), Munroe, P. (Patricia), Musk, A.W. (Arthur), Narisu, N. (Narisu), Navis, G. (Gerjan), Nicholson, G. (Ggeorge), Nohr, C. (Christian), Ong, K. (Ken), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Palotie, A. (Aarno), Peden, J. (John), Pedersen, N.L. (Nancy), Peters, A. (Annette), Polasek, O. (Ozren), Pouta, A. (Anneli), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Pütter, C. (Carolin), Radhakrishnan, A. (Aparna), Raitakari, O. (Olli), Rendon, A. (Augusto), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Saaristo, T. (Timo), Sambrook, J.G. (Jennifer), Sanders, A.R. (Alan), Sanna, S. (Serena), Saramies, J. (Jouko), Schipf, S. (Sabine), Schreiber, S. (Stefan), Schunkert, H. (Heribert), Shin, S.-Y., Signorini, S. (Stefano), Sinisalo, J. (Juha), Skrobek, B. (Boris), Soranzo, N. (Nicole), Stancáková, A. (Alena), Stark, K. (Klaus), Stephens, J. (Jonathan), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Stumvoll, M. (Michael), Swift, A.J. (Amy), Theodoraki, E.V. (Eirini), Thorand, B. (Barbara), Tregouet, D.-A. (David-Alexandre), Tremoli, E. (Elena), Klauw, M.M. (Melanie) van der, Meurs, J.B.J. (Joyce) van, Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Waeber, G. (Gérard), Wang, Z. (Zhaoming), Widen, E. (Elisabeth), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Winkelmann, B., Witteman, J.C.M. (Jacqueline), Wolffenbuttel, B.H.R. (Bruce), Wong, A. (Andrew), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Amouyel, P. (Philippe), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Caulfield, M. (Mark), Chanock, S.J. (Stephen), Cupples, L.A. (Adrienne), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Eriksson, J.G. (Johan), Franks, P.W. (Paul), Froguel, P. (Philippe), Gieger, C. (Christian), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hengstenberg, C. (Christian), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hinney, A. (Anke), Hofman, A. (Albert), Hovingh, G.K. (Kees), Hveem, K. (Kristian), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Jöckel, K.-H. (Karl-Heinz), Keinanen-Kiukaanniemi, S. (Sirkka), Kiemeney, L.A.L.M. (Bart), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Levinson, D.F. (Douglas), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Morris, A.D. (Andrew), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Ouwehand, W.H. (Willem), Palmer, C. (Cameron), Penninx, B.W.J.H. (Brenda), Power, C. (Christopher), Province, M.A. (Mike), Psaty, B.M. (Bruce), Qi, L. (Lu), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Snieder, H. (Harold), Sorensen, H.G., Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Tönjes, A. (Anke), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Harst, P. (Pim) van der, Vollenweider, P. (Peter), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wichmann, H.E. (Heinz Erich), Wilson, J.F. (James F), Abecasis, G.R. (Gonçalo), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Fox, C. (Craig), Frayling, T.M. (Timothy), Groop, L. (Leif), Haritunian, T. (Talin), Heid, I.M. (Iris), Hunter, D. (David), Kaplan, R.C. (Robert), Karpe, F. (Fredrik), Moffatt, M.F. (Miriam), Mohlke, K.L. (Karen), O´Connell, J.R., Pawitan, Y. (Yudi), Schadt, E.E. (Eric), Schlessinger, D. (David), Steinthorsdottir, V. (Valgerdur), Strachan, D.P. (David), Thorsteinsdottir, U. (Unnur), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Di Blasio, A.M. (Anna Maria), Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia), Meyre, D. (David), Scherag, A. (Andre), McCarthy, M.I. (Mark), Speliotes, E.K. (Elizabeth), North, K.E. (Kari), Loos, R.J.F. (Ruth), Ingelsson, E. (Erik), Berndt, S.I. (Sonja), Gustafsson, S. (Stefan), Mägi, R. (Reedik), Ganna, A. (Andrea), Wheeler, E. (Eleanor), Feitosa, M.F. (Mary Furlan), Justice, A.E. (Anne), Monda, K.L. (Keri), Croteau-Chonka, D.C. (Damien), Day, F.R. (Felix), Esko, T. (Tõnu), Fall, M. (Magnus), Ferreira, T. (Teresa), Gentilini, D. (Davide), Jackson, A.U. (Anne), Luan, J., Randall, J.C. (Joshua), Vedantam, S. (Sailaja), Willer, C.J. (Cristen), Winkler, T.W. (Thomas), Wood, A.R. (Andrew), Workalemahu, T. (Tsegaselassie), Hu, Y.-J. (Yi-Juan), Lee, S.H. (Sang Hong), Liang, L. (Liming), Lin, D.Y. (Dan), Min, J. (Josine), Neale, B.M. (Benjamin), Thorleifsson, G. (Gudmar), Yang, J. (Jian), Albrecht, E. (Eva), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Cadby, G. (Gemma), Heijer, M. (Martin) den, Eklund, N. (Niina), Fischer, K. (Krista), Goel, A. (Anuj), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jarick, I. (Ivonne), Johansson, A. (Åsa), Johnson, T. (Toby), Kanoni, S. (Stavroula), Kleber, M.E. (Marcus), König, I.R. (Inke), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lamina, C. (Claudia), Lecoeur, C. (Cécile), Li, G. (Guo), Mangino, M. (Massimo), McArdle, W.L. (Wendy), Medina-Gomez, M.C. (Carolina), Müller-Nurasyid, M. (Martina), Ngwa, J.S., Nolte, I.M. (Ilja), Paternoster, L. (Lavinia), Pechlivanis, S. (Sonali), Perola, M. (Markus), Peters, M.J. (Marjolein), Preuss, M. (Michael), Rose, L.M. (Lynda), Shi, J. (Jianxin), Shungin, D. (Dmitry), Smith, A.V. (Davey), Strawbridge, R.J. (Rona), Surakka, I. (Ida), Teumer, A. (Alexander), Trip, M.D. (Mieke), Tyrer, J.P. (Jonathan), Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Waite, L. (Lindsay), Zhao, J.H. (Jing Hua), Absher, D. (Devin), Asselbergs, F.W. (Folkert), Atalay, M. (Mustafa), Attwood, A.P. (Antony), Balmforth, A.J. (Anthony), Basart, D.C.G. (Dick), Beilby, J.P. (John), Bonnycastle, L.L. (Lori), Brambilla, P. (Paolo), Bruinenberg, M. (M.), Campbell, H. (Harry), Chasman, D.I. (Daniel), Chines, P.S. (Peter), Collins, F.S. (Francis), Connell, J. (John), Cookson, W.O. (William), Faire, U. (Ulf) de, Vegt, F. (Femmie) de, Dei, M. (Mariano), Dimitriou, M. (Maria), Edkins, T. (Ted), Estrada Gil, K. (Karol), Evans, D.M. (David), Farrall, M. (Martin), Ferrario, F. (Franco), Ferrières, J. (Jean), Franke, L. (Lude), Frau, F. (Francesca), Gejman, P.V. (Pablo), Grallert, H. (Harald), Grönberg, H. (Henrik), Gudnason, V. (Vilmundur), Hall, A. (Anne), Hall, A.S. (Alistair), Hartikainen, A.L., Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Heath, A.C. (Andrew), Hebebrand, J. (Johannes), Homuth, G. (Georg), Hu, F.B. (Frank), Hunt, S.E. (Sarah), Hyppönen, E. (Elina), Iribarren, C. (Carlos), Jacobs, K.B. (Kevin), Jansson, J.-O. (John-Olov), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Kee, F. (F.), Khaw, K-T. (Kay-Tee), Kivimaki, M. (Mika), Koenig, W. (Wolfgang), Kraja, A. (Aldi), Kumari, M. (Meena), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Laitinen, J. (Jaana), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lind, L. (Lars), Lindstrom, J. (Jaana), Liu, J. (Jianjun), Liuzzi, A. (Antonio), Lokki, M.L., Lorentzon, M. (Mattias), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Manunta, P. (Paolo), Marek, D. (Diana), März, W. (Winfried), Leach, I.M. (Irene Mateo), McKnight, B. (Barbara), Medland, S.E. (Sarah), Mihailov, E. (Evelin), Milani, L. (Lili), Montgomery, G.W. (Grant), Mooser, V. (Vincent), Mühleisen, T.W. (Thomas), Munroe, P. (Patricia), Musk, A.W. (Arthur), Narisu, N. (Narisu), Navis, G. (Gerjan), Nicholson, G. (Ggeorge), Nohr, C. (Christian), Ong, K. (Ken), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Palotie, A. (Aarno), Peden, J. (John), Pedersen, N.L. (Nancy), Peters, A. (Annette), Polasek, O. (Ozren), Pouta, A. (Anneli), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Pütter, C. (Carolin), Radhakrishnan, A. (Aparna), Raitakari, O. (Olli), Rendon, A. (Augusto), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Saaristo, T. (Timo), Sambrook, J.G. (Jennifer), Sanders, A.R. (Alan), Sanna, S. (Serena), Saramies, J. (Jouko), Schipf, S. (Sabine), Schreiber, S. (Stefan), Schunkert, H. (Heribert), Shin, S.-Y., Signorini, S. (Stefano), Sinisalo, J. (Juha), Skrobek, B. (Boris), Soranzo, N. (Nicole), Stancáková, A. (Alena), Stark, K. (Klaus), Stephens, J. (Jonathan), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Stumvoll, M. (Michael), Swift, A.J. (Amy), Theodoraki, E.V. (Eirini), Thorand, B. (Barbara), Tregouet, D.-A. (David-Alexandre), Tremoli, E. (Elena), Klauw, M.M. (Melanie) van der, Meurs, J.B.J. (Joyce) van, Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Waeber, G. (Gérard), Wang, Z. (Zhaoming), Widen, E. (Elisabeth), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Winkelmann, B., Witteman, J.C.M. (Jacqueline), Wolffenbuttel, B.H.R. (Bruce), Wong, A. (Andrew), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Amouyel, P. (Philippe), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Caulfield, M. (Mark), Chanock, S.J. (Stephen), Cupples, L.A. (Adrienne), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Eriksson, J.G. (Johan), Franks, P.W. (Paul), Froguel, P. (Philippe), Gieger, C. (Christian), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hengstenberg, C. (Christian), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hinney, A. (Anke), Hofman, A. (Albert), Hovingh, G.K. (Kees), Hveem, K. (Kristian), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Jöckel, K.-H. (Karl-Heinz), Keinanen-Kiukaanniemi, S. (Sirkka), Kiemeney, L.A.L.M. (Bart), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Levinson, D.F. (Douglas), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Morris, A.D. (Andrew), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Ouwehand, W.H. (Willem), Palmer, C. (Cameron), Penninx, B.W.J.H. (Brenda), Power, C. (Christopher), Province, M.A. (Mike), Psaty, B.M. (Bruce), Qi, L. (Lu), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Snieder, H. (Harold), Sorensen, H.G., Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Tönjes, A. (Anke), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Harst, P. (Pim) van der, Vollenweider, P. (Peter), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wichmann, H.E. (Heinz Erich), Wilson, J.F. (James F), Abecasis, G.R. (Gonçalo), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Fox, C. (Craig), Frayling, T.M. (Timothy), Groop, L. (Leif), Haritunian, T. (Talin), Heid, I.M. (Iris), Hunter, D. (David), Kaplan, R.C. (Robert), Karpe, F. (Fredrik), Moffatt, M.F. (Miriam), Mohlke, K.L. (Karen), O´Connell, J.R., Pawitan, Y. (Yudi), Schadt, E.E. (Eric), Schlessinger, D. (David), Steinthorsdottir, V. (Valgerdur), Strachan, D.P. (David), Thorsteinsdottir, U. (Unnur), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Di Blasio, A.M. (Anna Maria), Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia), Meyre, D. (David), Scherag, A. (Andre), McCarthy, M.I. (Mark), Speliotes, E.K. (Elizabeth), North, K.E. (Kari), Loos, R.J.F. (Ruth), and Ingelsson, E. (Erik)
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Published: 2013
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49. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author: Huang, J. (Jian), Sabater-Lleal, M. (Maria), Asselbergs, F.W. (Folkert), Tregouet, D.-A. (David-Alexandre), Shin, S.-Y., Ding, J. (Jingzhong), Baumert, J. (Jens), Oudot-Mellakh, T. (Tiphaine), Folkersen, L. (Lasse), Johnson, A.D. (Andrew), Smith, N.L. (Nicholas), Williams, S.M. (Scott), Ikram, M.A. (Arfan), Kleber, M.E. (Marcus), Becker, D.M. (Diane), Truong, V. (Vinh), Mychaleckyj, J.C. (Josyf), Tang, W. (Weihong), Yang, Q. (Qiong Fang), Sennblad, B. (Bengt), Moore, J.H. (Jason), Williams, F.M. (Frances), Dehghan, A. (Abbas), Silbernagel, G. (Günther), Schrijvers, E.M.C. (Elisabeth M. C.), Smith, S. (Sarah), Karakas, M. (Mahir), Tofler, G.H. (Geoffrey), Silveira, A. (Angela), Navis, G. (Gerjan), Lohman, K. (Kurt), Chen, M-H. (Ming-Huei), Peters, A. (Annette), Goel, A. (Anuj), Hopewell, J., Chambers, J.C. (John), Saleheen, D., Lundmark, P. (Per), Psaty, B.M. (Bruce), Strawbridge, R.J. (Rona), Boehm, B.O. (Bernhard), Carter, A.M. (Angela M.), Meisinger, C. (Christa), Peden, J. (John), Bis, J.C. (Joshua), McKnight, B. (Barbara), Öhrvik, J. (John), Taylor, K.D. (Kent), Franzosi, M., Seedorf, U. (Udo), Collins, R. (Rory), Franco-Cereceda, A. (Anders), Syvanen, A.C., Goodall, A.H. (Alison), Yanek, L.R. (Lisa), Cushman, M. (Mary Ann), Müller-Nurasyid, M. (Martina), Folsom, A.R. (Aaron), Basu, S. (Saonli), Aleksic, N. (Nena), Gilst, W.H. (Wiek) van, Kooner, J.S. (Jaspal), Hofman, A. (Albert), Danesh, J. (John), Clarke, R. (Robert), Meigs, J.B. (James), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Klopp, N. (Norman), Harris, T.B. (Tamara), Winkelmann, B., Grant, P.J. (Peter J.), Hillege, H.L. (Hans), Watkins, H. (Hugh), Spector, T.D. (Timothy), Becker, L.C. (Lewis), Tracy, R.P. (Russell), März, W. (Winfried), Uitterlinden, A.G. (André), Eriksson, P. (Per), Cambien, F. (François), Morange, P.-E. (P.), Koenig, W. (Wolfgang), Soranzo, N. (Nicole), Harst, P. (Pim) van der, Liu, Y. (YongMei), O'Donnell, C.J. (Christopher), Hamsten, A. (Anders), Huang, J. (Jian), Sabater-Lleal, M. (Maria), Asselbergs, F.W. (Folkert), Tregouet, D.-A. (David-Alexandre), Shin, S.-Y., Ding, J. (Jingzhong), Baumert, J. (Jens), Oudot-Mellakh, T. (Tiphaine), Folkersen, L. (Lasse), Johnson, A.D. (Andrew), Smith, N.L. (Nicholas), Williams, S.M. (Scott), Ikram, M.A. (Arfan), Kleber, M.E. (Marcus), Becker, D.M. (Diane), Truong, V. (Vinh), Mychaleckyj, J.C. (Josyf), Tang, W. (Weihong), Yang, Q. (Qiong Fang), Sennblad, B. (Bengt), Moore, J.H. (Jason), Williams, F.M. (Frances), Dehghan, A. (Abbas), Silbernagel, G. (Günther), Schrijvers, E.M.C. (Elisabeth M. C.), Smith, S. (Sarah), Karakas, M. (Mahir), Tofler, G.H. (Geoffrey), Silveira, A. (Angela), Navis, G. (Gerjan), Lohman, K. (Kurt), Chen, M-H. (Ming-Huei), Peters, A. (Annette), Goel, A. (Anuj), Hopewell, J., Chambers, J.C. (John), Saleheen, D., Lundmark, P. (Per), Psaty, B.M. (Bruce), Strawbridge, R.J. (Rona), Boehm, B.O. (Bernhard), Carter, A.M. (Angela M.), Meisinger, C. (Christa), Peden, J. (John), Bis, J.C. (Joshua), McKnight, B. (Barbara), Öhrvik, J. (John), Taylor, K.D. (Kent), Franzosi, M., Seedorf, U. (Udo), Collins, R. (Rory), Franco-Cereceda, A. (Anders), Syvanen, A.C., Goodall, A.H. (Alison), Yanek, L.R. (Lisa), Cushman, M. (Mary Ann), Müller-Nurasyid, M. (Martina), Folsom, A.R. (Aaron), Basu, S. (Saonli), Aleksic, N. (Nena), Gilst, W.H. (Wiek) van, Kooner, J.S. (Jaspal), Hofman, A. (Albert), Danesh, J. (John), Clarke, R. (Robert), Meigs, J.B. (James), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Klopp, N. (Norman), Harris, T.B. (Tamara), Winkelmann, B., Grant, P.J. (Peter J.), Hillege, H.L. (Hans), Watkins, H. (Hugh), Spector, T.D. (Timothy), Becker, L.C. (Lewis), Tracy, R.P. (Russell), März, W. (Winfried), Uitterlinden, A.G. (André), Eriksson, P. (Per), Cambien, F. (François), Morange, P.-E. (P.), Koenig, W. (Wolfgang), Soranzo, N. (Nicole), Harst, P. (Pim) van der, Liu, Y. (YongMei), O'Donnell, C.J. (Christopher), and Hamsten, A. (Anders)
Published: 2012
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50. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

Author: Sofat, R. (Reecha), Hingorani, A. (Aroon), Smeeth, L. (Liam), Humphries, S.E. (Steve), Talmud, P.J., Cooper, J. (Jim), Shah, T. (Tina), Sandhu, M.S. (Manjinder), Ricketts, S.L. (Sally), Boekholdt, S.M. (Matthijs), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Kumari, M. (Meena), Kivimaki, M. (Mika), Marmot, M. (Michael), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Dullaart, R.P.F. (Robin), Navis, G. (Gerjan), Veldhuisen, D.J. (Dirk) van, Gilst, W.H. (Wiek) van, Thompson, J.F. (John), McCaskie, P. (Pamela), Palmer, C. (Cameron), Arca, M. (Marcello), Quagliarini, F. (Fabiana), Gaudio, C. (Carlo), Cambien, F. (François), Nicaud, V., Poirer, O. (Odette), Gudnason, V. (Vilmundur), Isaacs, A.J. (Aaron), Witteman, J.C.M. (Jacqueline), Tikka-Kleemola, P. (Päivi), Pencina, M. (Michael), Vasan, R.S. (Ramachandran Srini), D'Agostino, R.B. (Ralph), Ordovas, J.M. (Jose), Li, T.Y. (Tricia), Kakko, S. (Sakari), Kauma, H. (Heikki), Savolainen, M.J. (Markku), Kesäniemi, Y.A. (Antero), Sandhofer, A. (Anton), Paulweber, B. (Bernhard), Sorli, J.V. (Jose), Goto, A. (Akimoto), Yokoyama, S. (Shinji), Okumura, K. (Kenji), Horne, B.D. (Benjamin), Packard, C. (Chris), Freeman, D. (Dilys), Ford, I. (Ian), Sattar, N. (Naveed), McCormack, V. (Valerie), Lawlor, D.A. (Debbie), Ebrahim, S. (Shanil), Smith, A.V. (Davey), Kastelein, J.J.P. (John), Deanfield, J. (John), Casas, J.P. (Juan), Sofat, R. (Reecha), Hingorani, A. (Aroon), Smeeth, L. (Liam), Humphries, S.E. (Steve), Talmud, P.J., Cooper, J. (Jim), Shah, T. (Tina), Sandhu, M.S. (Manjinder), Ricketts, S.L. (Sally), Boekholdt, S.M. (Matthijs), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Kumari, M. (Meena), Kivimaki, M. (Mika), Marmot, M. (Michael), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Dullaart, R.P.F. (Robin), Navis, G. (Gerjan), Veldhuisen, D.J. (Dirk) van, Gilst, W.H. (Wiek) van, Thompson, J.F. (John), McCaskie, P. (Pamela), Palmer, C. (Cameron), Arca, M. (Marcello), Quagliarini, F. (Fabiana), Gaudio, C. (Carlo), Cambien, F. (François), Nicaud, V., Poirer, O. (Odette), Gudnason, V. (Vilmundur), Isaacs, A.J. (Aaron), Witteman, J.C.M. (Jacqueline), Tikka-Kleemola, P. (Päivi), Pencina, M. (Michael), Vasan, R.S. (Ramachandran Srini), D'Agostino, R.B. (Ralph), Ordovas, J.M. (Jose), Li, T.Y. (Tricia), Kakko, S. (Sakari), Kauma, H. (Heikki), Savolainen, M.J. (Markku), Kesäniemi, Y.A. (Antero), Sandhofer, A. (Anton), Paulweber, B. (Bernhard), Sorli, J.V. (Jose), Goto, A. (Akimoto), Yokoyama, S. (Shinji), Okumura, K. (Kenji), Horne, B.D. (Benjamin), Packard, C. (Chris), Freeman, D. (Dilys), Ford, I. (Ian), Sattar, N. (Naveed), McCormack, V. (Valerie), Lawlor, D.A. (Debbie), Ebrahim, S. (Shanil), Smith, A.V. (Davey), Kastelein, J.J.P. (John), Deanfield, J. (John), and Casas, J.P. (Juan)
Abstract: Background: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI-0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI-0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action
Published: 2010
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