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1. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author: Barbara McKnight, Martina Müller-Nurasyid, Raha Pazoki, Michael W.T. Tanck, Thomas Engstrøm, Arthur A.M. Wilde, Man Li, Martin VanDenburgh, Marieke T. Blom, Reza Jabbari, Thomas Meitinger, Philippe Goyette, Anna Moes, Rebecca N. Mitchell, Christine M. Albert, Aravinda Chakravarti, Dan E. Arking, Jean-Claude Tardif, Rozenn N. Lemaitre, Foram N. Ashar, Pui-Yan Kwok, Frank D. Kolodgie, Jacob Tfelt-Hansen, Renu Virmani, Susan R. Heckbert, Angel C.Y. Mak, David S. Siscovick, Vinicius Tragante, Xavier Jouven, Hanno L. Tan, John D. Rioux, Mark Eijgelsheim, Ronald J. Prineas, Nona Sotoodehnia, Xiaoqing Zhao, Stefan A. Escher, Heikki V. Huikuri, Bruce M. Psaty, Charlotte Glinge, Albert Hofman, Oscar H. Franco, Florence Dumas, Bruno H. Stricker, M. Juhani Junttila, Folkert W. Asselbergs, Josef Coresh, Christopher J. O'Donnell, Paul W. Franks, Shih-Jen Hwang, Veikko Salomaa, Jan-Håkan Jansson, Stefan Kääb, Christopher Newton-Cheh, Joseph J. Maleszewski, Paul I.W. de Bakker, Jennifer A. Brody, Aki S. Havulinna, André G. Uitterlinden, Georg Ehret, Jerome I. Rotter, Thomas Lumley, Connie R. Bezzina, Marc K. Halushka, Sara L. Pulit, Epidemiology, Internal Medicine, Ehret, Georg Benedikt, Cardiology, Epidemiology and Data Science, APH - Methodology, ACS - Heart failure & arrhythmias, and APH - Health Behaviors & Chronic Diseases
Subjects: Male, Genome-wide association study, Coronary Artery Disease, Cardiorespiratory Medicine and Haematology, Arrhythmias, 030204 cardiovascular system & hematology, VARIANTS, Cardiovascular, Bioinformatics, Body Mass Index, Sudden cardiac death, Coronary artery disease, 0302 clinical medicine, Risk Factors, 2.1 Biological and endogenous factors, Medicine, 030212 general & internal medicine, Family history, Aetiology, Cardiac/genetics/physiopathology, reproductive and urinary physiology, POPULATION, 0303 health sciences, education.field_of_study, Coronary Artery Disease/genetics, ATHEROSCLEROSIS-RISK, DEATH, hemic and immune systems, Mendelian Randomization Analysis, Single Nucleotide, 3. Good health, Death, Heart Disease, MENDELIAN RANDOMIZATION, Medical genetics, Female, FIBRILLATION, medicine.symptom, Cardiology and Cardiovascular Medicine, Cardiac, Cardiac/etiology, medicine.medical_specialty, Clinical Sciences, Population, Single-nucleotide polymorphism, 610 Medicine & health, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Risk Assessment, Heart Conduction System/physiopathology, 03 medical and health sciences, Sex Factors, Sudden cardiac arrest, Clinical Research, Heart Conduction System, 360 Social problems & social services, RISK-FACTOR, Mendelian randomization, Genetics, Journal Article, Humans, INTERVAL, Polymorphism, Risk Assessment/methods, education, Heart Disease - Coronary Heart Disease, 030304 developmental biology, business.industry, Prevention, Human Genome, Arrhythmias, Cardiac, medicine.disease, Sudden, Genetic architecture, Good Health and Well Being, Death, Sudden, Cardiac, Cardiovascular System & Hematology, business
Abstract: BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.MethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.ResultsNo variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in highrisk populations and the general community.
Published: 2018

2. Missing heritability: is the gap closing? An analysis of 32 complex traits in the Lifelines Cohort Study

Author: Marianne G. Rots, Paul I.W. de Bakker, H. Marike Boezen, Harold Snieder, Pim van der Harst, Lude Franke, Behrooz Z. Alizadeh, Bruce H. R. Wolffenbuttel, Cisca Wijmenga, Marcel Bruinenberg, Ilja M. Nolte, Ronald P. Stolk, Dirkje S. Postma, Gerjan Navis, Peter J. van der Most, Morris A. Swertz, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Value, Affordability and Sustainability (VALUE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: 0301 basic medicine, LOCI, Blood Pressure, BLOOD-PRESSURE, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Genetic correlation, Article, KIDNEY-FUNCTION, 03 medical and health sciences, Quantitative Trait, Heritable, 0302 clinical medicine, Heart Rate, Missing heritability problem, Genetics, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Human height, Closing (morphology), Genetics (clinical), Genes, Dominant, Respiration, COMMON VARIANTS, Blood Cell Count, BODY-MASS INDEX, INDIVIDUALS, Phenotype, 030104 developmental biology, BIOLOGICAL PATHWAYS, HUMAN HEIGHT, GENE-CENTRIC METAANALYSES, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography, Cohort study
Abstract: Despite the recent explosive rise in number of genetic markers for complex disease traits identified in genome-wide association studies, there is still a large gap between the known heritability of these traits and the part explained by these markers. To gauge whether this 'heritability gap' is closing, we first identified genome-wide significant SNPs from the literature and performed replication analyses for 32 highly relevant traits from five broad disease areas in 13 436 subjects of the Lifelines Cohort. Next, we calculated the variance explained by multi-SNP genetic risk scores (GRSs) for each trait, and compared it to their broad-and narrow-sense heritabilities captured by all common SNPs. The majority of all previously-associated SNPs (median = 75%) were significantly associated with their respective traits. All GRSs were significant, with unweighted GRSs generally explaining less phenotypic variance than weighted GRSs, for which the explained variance was highest for height (15.5%) and varied between 0.02 and 6.7% for the other traits. Broad-sense common-SNP heritability estimates were significant for all traits, with the additive effect of common SNPs explaining 48.9% of the variance for height and between 5.6 and 39.2% for the other traits. Dominance effects were uniformly small (0-1.5%) and not significant. On average, the variance explained by the weighted GRSs accounted for only 10.7% of the common-SNP heritability of the 32 traits. These results indicate that GRSs may not yet be ready for accurate personalized prediction of complex disease traits limiting widespread adoption in clinical practice.
Published: 2017

3. Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

Author: Yalda Jamshidi, Paul I.W. de Bakker, J. Wouter Jukema, Ilaria Gandin, Monika Stoll, Christopher P. Nelson, Moritz F. Sinner, Eco J. C. de Geus, André G. Uitterlinden, Jan A. Kors, Vilmundur Gudnason, Sheila Ulivi, Jouke-Jan Hottenga, Terho Lehtimäki, Antonietta Robino, Mark Eijgelsheim, Annamaria Iorio, Niek Verweij, Martina Müller-Nurasyid, Ian Ford, Hao Mei, James G. Wilson, Albert V. Smith, Thomas Meitinger, Gianfranco Sinagra, Claudia T. Silva Aldana, Maartje N. Niemeijer, Torben Hansen, Allan Linneberg, Jennifer A. Brody, Pim van der Harst, Stella Trompet, Paolo Gasparini, Bram P. Prins, Stefan Kääb, Hamdi Mbarek, Alvaro Alonso, Leanne M. Hall, Helen R. Warren, Dan E. Arking, Peter W. Macfarlane, Annette Peters, Olli T. Raitakari, Daiane Hemerich, Mark J. Caulfield, Folkert W. Asselbergs, Dorret I. Boomsma, Aaron Isaacs, Bruno H. Stricker, Tamara B. Harris, Susan R. Heckbert, Jessica van Setten, Niels Grarup, Patricia B. Munroe, Leo-Pekka Lyytikäinen, Nilesh J. Samani, Cornelia M. van Duijn, Elsayed Z. Soliman, Nona Sotoodehnia, Jørgen K. Kanters, Melanie Waldenberger, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, Erasmus MC other, Epidemiology, Medical Informatics, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, van Setten, Jessica, Verweij, Niek, Mbarek, Hamdi, Niemeijer, Maartje N., Trompet, Stella, Arking, Dan E., Brody, Jennifer A., Gandin, Ilaria, Grarup, Niel, Hall, Leanne M., Hemerich, Daiane, Lyytikäinen, Leo-Pekka, Mei, Hao, Müller-Nurasyid, Martina, Prins, Bram P., Robino, Antonietta, Smith, Albert V., Warren, Helen R., Asselbergs, Folkert W., Boomsma, Dorret I., Caulfield, Mark J., Eijgelsheim, Mark, Ford, Ian, Hansen, Torben, Harris, Tamara B., Heckbert, Susan R., Hottenga, Jouke-Jan, Iorio, Anita, Kors, Jan A., Linneberg, Allan, Macfarlane, Peter W., Meitinger, Thoma, Nelson, Christopher P., Raitakari, Olli T., Silva Aldana, Claudia T., Sinagra, Gianfranco, Sinner, Moritz, Soliman, Elsayed Z., Stoll, Monika, Uitterlinden, Andre, van Duijn, Cornelia M., Waldenberger, Melanie, Alonso, Alvaro, Gasparini, Paolo, Gudnason, Vilmundur, Jamshidi, Yalda, Kääb, Stefan, Kanters, Jørgen K., Lehtimäki, Terho, Munroe, Patricia B., Peters, Annette, Samani, Nilesh J., Sotoodehnia, Nona, Ulivi, Sheila, Wilson, James G., de Geus, Eco J. C., Jukema, J. Wouter, Stricker, Bruno, van der Harst, Pim, de Bakker, Paul I. W., Isaacs, Aaron, Cardiovascular Centre (CVC), Biochemie, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Netherlands Twin Register (NTR), Genetics, Genetics (clinical), PROTEIN, Genome-wide association study, Quantitative trait, Genome-wide association studies, ANNOTATION, Gene locus, Electrocardiography, Computer model, Netherlands, Priority journal, Allele, 0303 health sciences, Genome, Rr interval, 030305 genetics & heredity, COMMON VARIANTS, ddc, GLUCOCORTICOID-RECEPTOR, Qrs interval, Female, Cohort analysis, Erfðarannsóknir, PHOSPHOLAMBAN, Human, QT INTERVAL DURATION, Genotype, Heart rate, HEART-RATE, Exon, Single-nucleotide polymorphism, Major clinical study, Biology, Quantitative trait locus, Dutchman, Polymorphism, Single Nucleotide, QT interval, Article, Sample, 03 medical and health sciences, QRS complex, Genetic, SDG 3 - Good Health and Well-being, Humans, PR interval, Gene mapping, Genetic association, MUTATIONS, Follow up, CONTRACTILITY, DNA-rannsóknir, R1, Gene frequency, POLYMORPHISM, Electrocardiogram, Single nucleotide polymorphism, Minor allele frequency, Genetic Loci, Meta analysis, Qt interval, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes., Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre.
Published: 2019

4. Exome-chip association analysis of intracranial aneurysms

Author: Ynte M. Ruigrok, Gabriel J.E. Rinkel, Dongbing Lai, Paul I.W. de Bakker, Femke N.G. van 't Hof, Jessica van Setten, Ilonca Vaartjes, Tatiana Foroud, Michiel L. Bots, Joseph P. Broderick, and Daniel Woo
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Adolescent, Genotype, Population, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, symbols.namesake, Young Adult, 0302 clinical medicine, Gene Frequency, Internal medicine, medicine, Humans, Exome, Genetic Predisposition to Disease, education, Allele frequency, Fisher's exact test, Genetic association, Aged, Netherlands, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, education.field_of_study, Extracellular Matrix Proteins, Calcium-Binding Proteins, Case-control study, Intracranial Aneurysm, Middle Aged, Minor allele frequency, 030104 developmental biology, Case-Control Studies, symbols, Female, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: ObjectiveTo investigate to what extent low-frequency genetic variants (with minor allele frequencies MethodsOne thousand fifty-six patients with IA and 2,097 population-based controls from the Netherlands were genotyped with the Illumina HumanExome BeadChip. After quality control (QC) of samples and single nucleotide variants (SNVs), we conducted a single variant analysis using the Fisher exact test. We also performed the variable threshold (VT) test and the sequence kernel association test (SKAT) at different minor allele count (MAC) thresholds of >5 and >0 to test the hypothesis that multiple variants within the same gene are associated with IA risk. Significant results were tested in a replication cohort of 425 patients with IA and 311 controls, and results of the 2 cohorts were combined in a meta-analysis.ResultsAfter QC, 995 patients with IA and 2,080 controls remained for further analysis. The single variant analysis comprising 46,534 SNVs did not identify significant loci at the genome-wide level. The gene-based tests showed a statistically significant association for fibulin 2 (FBLN2) (best p = 1 × 10−6 for the VT test, MAC >5). Associations were not statistically significant in the independent but smaller replication cohort (p > 0.57) but became slightly stronger in a meta-analysis of the 2 cohorts (best p = 4.8 × 10−7 for the SKAT, MAC ≥1).ConclusionGene-based tests indicated an association for FBLN2, a gene encoding an extracellular matrix protein implicated in vascular wall remodeling, but independent validation in larger cohorts is warranted. We did not identify any significant associations for single low-frequency genetic variants.
Published: 2019

5. Cystatin C and Cardiovascular Disease

Author: Heribert Schunkert, Wolfgang Koenig, Jessica van Setten, Meena Kumari, Johan Ärnlöv, J. Wouter Jukema, Vinicius Tragante, Alanna C. Morrison, Bradford B. Worrall, Brendan J. Keating, Alexander Teumer, Vilmantas Giedraitis, Tom Wilsgaard, Nilesh J. Samani, Barbara Thorand, Patricia B. Munroe, Rainer Malik, Melanie Waldenberger, Christopher P. Nelson, Sebastian E. Baumeister, Aroon D. Hingorani, Stéphanie Debette, Tove Fall, Patrik K. E. Magnusson, Nora Franceschini, Anders Larsson, Andrew P. Morris, Folkert W. Asselbergs, Maryam Kavousi, Oscar H. Franco, Jeanette Erdmann, Jonathan Marchini, Mika Kivimäki, Ivana Išgum, Fotios Drenos, N. Charlotte Onland-Moret, Bjørn Odvar Eriksen, Aicha Soumare, Christopher J. O'Donnell, Ingrid Toft, Paul I.W. de Bakker, Johannes Arpegård, Jacqueline de Graaf, Abbas Dehghan, Delilah Zabaneh, Michael V. Holmes, Yvonne T. van der Schouw, Alexander P. Reiner, André G. Uitterlinden, Christa Meisinger, Janine F. Felix, Erik Ingelsson, Lars Lind, Martin Dichgans, Marcus Dörr, Albert Hofman, Sanaz Sedaghat, Lambertus A. Kiemeney, Joshua C. Bis, Jens Baumert, Tessel E. Galesloot, Hester M. den Ruijter, Gerard Pasterkamp, Annette Peters, Naveed Sattar, Nancy L. Pedersen, Pim van der Harst, Stella Trompet, Per Svensson, Riyaz S. Patel, Philippe Amouyel, and Sander W. van der Laan
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Population, Renal function, 030204 cardiovascular system & hematology, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mendelian randomization, medicine, education, education.field_of_study, biology, business.industry, Confounding, Mendelian Randomization Analysis, 3. Good health, Minor allele frequency, 030104 developmental biology, Cystatin C, biology.protein, Cystatin, Cardiology and Cardiovascular Medicine, business
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 x 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 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora 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 x 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. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license.
Published: 2016

6. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

Author: Mary Cushman, John M. Starr, Min-Lee Yang, Wei Zhou, Ursula M. Schick, Vinna Clavo, Bella Hu, Oluf Pedersen, Tarunveer S. Ahluwalia, John D. Eicher, Santhi K. Ganesh, Albert V. Smith, Abbas Dehghan, Rebecca D. Jackson, Ian J. Deary, Mika Kähönen, Megan L. Grove, Jennifer A. Brody, Judy Wang, Amanda M Rosa Di Sant, Lenore J. Launer, Stephen S. Rich, Jiansong Wang, David C. Liewald, Paul I.W. de Bakker, Jerome I. Rotter, Leo-Pekka Lyytikäinen, Ruth J. F. Loos, Leonard I. Zon, Bruce M. Psaty, Nora Franceschini, Erwin P. Bottinger, Ming-Huei Chen, Paul L. Auer, James G. Wilson, Raha Pazoki, Nathan Pankratz, Russell P. Tracy, Vilmundur Gudnason, André G. Uitterlinden, Mike A. Nalls, Kristina L. Hunker, Frank J. A. van Rooij, Eric Boerwinkle, Kent D. Taylor, Albert Hofman, Yan Zhang, Mattijs E. Numans, Yong Huo, Yi Zhou, Folkert W. Asselbergs, James S. Floyd, Richard L. Proia, Yingchang Lu, Terho Lehtimäki, Liguang Dong, Riccardo E. Marioni, Jette Bork-Jensen, Jia Jia, Tamara B. Harris, Vy M. Nguyen, Fernando Rivadeneira, Oscar H. Franco, Yongmei Liu, Niels Grarup, Andrew D. Johnson, L. Adrienne Cupples, Ani Manichaikul, Elliott J. Hagedorn, Xiaoling Zhang, Maarten Leusink, Torben Hansen, Ingrid B. Borecki, Maria L. Allende, Betina Heinsbek Thuesen, Allan Linneberg, Olli T. Raitakari, Christopher J. O'Donnell, Mary F. Feitosa, Melissa E. Garcia, Alexander P. Reiner, Epidemiology, and Internal Medicine
Subjects: Male, 0301 basic medicine, Erythrocytes, Quantitative Trait Loci, Population, Genome-wide association study, Quantitative trait locus, Hematocrit, Biology, Article, Mice, 03 medical and health sciences, White blood cell, Genotype, Ethnicity, Journal Article, Genetics, medicine, Animals, Humans, Exome, education, Zebrafish, Medicine(all), education.field_of_study, medicine.diagnostic_test, ta1184, ta3121, 3. Good health, Receptors, Lysosphingolipid, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Immunology, Erythrocyte Count, Absolute neutrophil count, Female, Genome-Wide Association Study
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

7. A general framework for meta-analyzing dependent studies with overlapping subjects in association mapping

Author: Jae Hoon Sul, Buhm Han, Dat Duong, Eleazar Eskin, Paul I.W. de Bakker, and Soumya Raychaudhuri
Subjects: 0301 basic medicine, Quantitative Trait Loci, Genome-wide association study, Computational biology, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Mice, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Genetics, Animals, Humans, Disease, Spurious relationship, Association mapping, Molecular Biology, Genetics (clinical), Genetic association, Gene Expression Profiling, Association Studies Articles, General Medicine, Models, Theoretical, Covariance, Random effects model, 030104 developmental biology, Case-Control Studies, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Meta-analysis strategies have become critical to augment power of genome-wide association studies (GWAS). To reduce genotyping or sequencing cost, many studies today utilize shared controls, and these individuals can inadvertently overlap among multiple studies. If these overlapping individuals are not taken into account in meta-analysis, they can induce spurious associations. In this article, we propose a general framework for adjusting association statistics to account for overlapping subjects within a meta-analysis. The key idea of our method is to transform the covariance structure of the data, so it can be used in downstream analyses. As a result, the strategy is very flexible and allows a wide range of meta-analysis methods, such as the random effects model, to account for overlapping subjects. Using simulations and real datasets, we demonstrate that our method has utility in meta-analyses of GWAS, as well as in a multi-tissue mouse expression quantitative trait loci (eQTL) study where our method increases the number of discovered eQTL by up to 19% compared with existing methods.
Published: 2016

8. 52 Genetic Loci Influencing Myocardial Mass

Author: Alan F. Wright, Cisca Wijmenga, Bruno H. Stricker, Peter W. Macfarlane, Edward G. Lakatta, Uwe Völker, Lenore J. Launer, Olli T. Raitakari, Stephan B. Felix, Toshiko Tanaka, Osorio Meirelles, Phil Barnett, Thomas Meitinger, Albert Hofman, Bosco Trinh, Tamara B. Harris, Peter M. Okin, Axel Visel, Teresa Nutile, Claudia T. Silva, Harry Campbell, Ilja M. Nolte, M. Fabiola Del Greco, Terho Lehtimäki, Shih-Jen Hwang, Alicia Lundby, Kamil Slowikowski, Luigi Ferrucci, Joshua C. Bis, Jerome I. Rotter, Nona Sotoodehnia, Sebastian Schafer, Igor Rudan, Ozren Polasek, Vinicius Tragante, Kenneth Rice, Connie R. Bezzina, Siegfried Perz, Aravinda Chakravarti, Paul I.W. de Bakker, Jared W. Magnani, Xinchen Wang, Yigal M. Pinto, Carsten Oliver Schmidt, Marcus Dörr, Peter P. Pramstaller, Jobanpreet Sehmi, Susan R. Heckbert, Richard B. Devereux, Jesper V. Olsen, Sheila Ulivi, Shane Neph, Peter M. Visscher, James F. Wilson, Alexander Nord, Tim D. Spector, Stefan Kääb, Elsayed Z. Soliman, Weihua Zhang, Lin Y. Chen, Pim van der Harst, Veronique Vitart, Anna F. Dominiczak, Mark Eijgelsheim, Pieter A. Doevendans, Josef M. Penninger, Jaspal S. Kooner, Georg Vogler, Patricia B. Munroe, Soumya Raychaudhuri, Christian Gieger, Harold Snieder, Annamaria Iorio, Caroline Hayward, Yalda Jamshidi, Mika Kähönen, Jessica van Setten, Wilko Spiering, Ian Ford, Andrew A. Hicks, John C. Chambers, Joel N. Hirschhorn, Matthew T. Maurano, Niek Verweij, Maria Grazia Pilia, Rolf Bodmer, Vilmundur Gudnason, Ben A. Oostra, Megan V. Cannon, Nilesh J. Samani, Bruce H. R. Wolffenbuttel, Annette Peters, David Schlessinger, Daniel Levy, J. Wouter Jukema, Malou van den Boogaard, Brendan M. Buckley, Arne Pfeufer, Michiel E. Adriaens, Rossella Sorice, Matthias Heinig, Jian Yang, Norbert Hubner, Stefania Bandinelli, André G. Uitterlinden, Hans L. Hillege, Martina Müller-Nurasyid, Andres Metspalu, Eric Haugen, Laurie A. Boyer, Ronald P. Stolk, Gonçalo R. Abecasis, Dan E. Arking, Manolis Kellis, Ishminder K. Kooner, Leo-Pekka Lyytikäinen, Dena G. Hernandez, Dirk J. van Veldhuisen, Len A. Pennacchio, Kasper Lage, Gianfranco Sinagra, Bruce M. Psaty, Christopher Newton-Cheh, Cornelia M. van Duijn, Stefania Nappo, Dalit May, Paolo Gasparini, Elizabeth J. Rossin, Rudolf A. de Boer, Alessandro P Delitala, Tõnu Esko, John A. Stamatoyannopoulos, Aaron Isaacs, Kathleen F. Kerr, Sian Tsung Tan, Tune H. Pers, Serena Sanna, Melanie Waldenberger, Marina Ciullo, Jorma Viikari, Vincent M. Christoffels, Bram P. Prins, Alvaro Alonso, Sandosh Padmanabhan, Harm-Jan Westra, Moritz F. Sinner, Albert V. Smith, Kirill V. Tarasov, Konstantin Strauch, Wiek H. van Gilst, Christian X. Weichenberger, Lude Franke, Folkert W. Asselbergs, Herman H W Silljé, Jan A. Kors, Irene Mateo Leach, Karl Andersen, Ivana Kolcic, Stella Trompet, Silvia Naitza, Broad Institute of MIT and Harvard, Raychaudhuri, Soumya, Sciences, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio, Biochemie, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Maastricht Centre for Systems Biology, Fysiologie, RS: Carim - B01 Blood proteins & engineering, Graduate School, ANS - Cellular & Molecular Mechanisms, ANS - Neuroinfection & -inflammation, AGEM - Endocrinology, metabolism and nutrition, Medical Biology, ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Intensive Care Medicine, Other Research, Cardiology, Ophthalmology, ACS - Amsterdam Cardiovascular Sciences, Center of Experimental and Molecular Medicine, AII - Inflammatory diseases, AII - Infectious diseases, ACS - Pulmonary hypertension & thrombosis, Gastroenterology and Hepatology, Experimental Immunology, Erasmus MC other, Epidemiology, Public Health, Medical Informatics, Clinical Genetics, Internal Medicine, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), van der Harst, Pim, van Setten, Jessica, Verweij, Niek, Vogler, Georg, Franke, Lude, Maurano, Matthew T., Wang, Xinchen, Mateo Leach, Irene, Eijgelsheim, Mark, Sotoodehnia, Nona, Hayward, Caroline, Sorice, Rossella, Meirelles, Osorio, Lyytikäinen, Leo Pekka, Polašek, Ozren, Tanaka, Toshiko, Arking, Dan E., Ulivi, Sheila, Trompet, Stella, Müller Nurasyid, Martina, Smith, Albert V., Dörr, Marcu, Kerr, Kathleen F., Magnani, Jared W., Fabiola, Del Greco M., Zhang, Weihua, Nolte, Ilja M., Silva, Claudia T., Padmanabhan, Sandosh, Tragante, Viniciu, Esko, Tõnu, Abecasis, Gonçalo R., Adriaens, Michiel E., Andersen, Karl, Barnett, Phil, Bis, Joshua C., Bodmer, Rolf, Buckley, Brendan M., Campbell, Harry, Cannon, Megan V., Chakravarti, Aravinda, Chen, Lin Y., Delitala, Alessandro, Devereux, Richard B., Doevendans, Pieter A., Dominiczak, Anna F., Ferrucci, Luigi, Ford, Ian, Gieger, Christian, Harris, Tamara B., Haugen, Eric, Heinig, Matthia, Hernandez, Dena G., Hillege, Hans L., Hirschhorn, Joel N., Hofman, Albert, Hubner, Norbert, Hwang, Shih Jen, Iorio, Annamaria, Kähönen, Mika, Kellis, Manoli, Kolcic, Ivana, Kooner, Ishminder K., Kooner, Jaspal S., Kors, Jan A., Lakatta, Edward G., Lage, Kasper, Launer, Lenore J., Levy, Daniel, Lundby, Alicia, Macfarlane, Peter W., May, Dalit, Meitinger, Thoma, Metspalu, Andre, Nappo, Stefania, Naitza, Silvia, Neph, Shane, Nord, Alex S., Nutile, Teresa, Okin, Peter M., Olsen, Jesper V., Oostra, Ben A., Penninger, Josef M., Pennacchio, Len A., Pers, Tune H., Perz, Siegfried, Peters, Annette, Pinto, Yigal M., Pfeufer, Arne, Pilia, Maria Grazia, Pramstaller, Peter P., Prins, Bram P., Raitakari, Olli T., Rice, Ken M., Rossin, Elizabeth J., Rotter, Jerome I., Schafer, Sebastian, Schlessinger, David, Schmidt, Carsten O., Sehmi, Jobanpreet, Silljé, Herman H. W., Sinagra, Gianfranco, Sinner, Moritz F., Slowikowski, Kamil, Soliman, Elsayed Z., Spector, Timothy D., Spiering, Wilko, Stamatoyannopoulos, John A., Stolk, Ronald P., Strauch, Konstantin, Tan, Sian Tsung, Tarasov, Kirill V., Trinh, Bosco, Uitterlinden, Andre G., van den Boogaard, Malou, van Duijn, Cornelia M., van Gilst, Wiek H., Viikari, Jorma S., Visscher, Peter M., Vitart, Veronique, Völker, Uwe, Waldenberger, Melanie, Weichenberger, Christian X., Westra, Harm Jan, Wijmenga, Cisca, Wolffenbuttel, Bruce H., Yang, Jian, Bezzina, Connie R., Munroe, Patricia B., Snieder, Harold, Wright, Alan F., Rudan, Igor, Boyer, Laurie A., Asselbergs, Folkert W., van Veldhuisen, Dirk J., Stricker, Bruno H., Psaty, Bruce M., Ciullo, Marina, Sanna, Serena, Lehtimäki, Terho, Wilson, James F., Bandinelli, Stefania, Alonso, Alvaro, Gasparini, Paolo, Jukema, J. Wouter, Kääb, Stefan, Gudnason, Vilmundur, Felix, Stephan B., Heckbert, Susan R., de Boer, Rudolf A., Newton Cheh, Christopher, Hicks, Andrew A., Chambers, John C., Jamshidi, Yalda, Visel, Axel, Christoffels, Vincent M., Isaacs, Aaron, Samani, Nilesh J., and de Bakker, Paul I. W.
Subjects: 0301 basic medicine, Biological functions, Qrs, Electrocardiogram, Genetic Association Study, Heart Failure, Left Ventricular Hypertrophy, Candidate gene, Cardiac & Cardiovascular Systems, heart failure, Genome-wide association study, ELECTROCARDIOGRAM, 030204 cardiovascular system & hematology, SCN5A gene, Gene locus, DISEASE, Muscle hypertrophy, In vivo study, 0302 clinical medicine, Sodium channel Nav1.5, REGULATORY DNA, Sodium channel Nav1.8, Cardiac muscle, CARDIAC-HYPERTROPHY, Priority journal, RISK, Genetics, Validation study, Heart, Genetic parameters, Reliability, Chromatin, left ventricular hypertrophy, GENOME, Drosophila melanogaster, Phenotype, medicine.anatomical_structure, 1117 Public Health And Health Services, genetic association study, Cardiology, cardiovascular system, HEART, Functional assessment, Histone modification, Cardiology and Cardiovascular Medicine, Genetic trait, Life Sciences & Biomedicine, Human, medicine.medical_specialty, Cardiomegaly, Locus (genetics), Major clinical study, electrocardiogram, European, QRS, 1102 Cardiovascular Medicine And Haematology, Article, 03 medical and health sciences, QRS complex, LEFT-VENTRICULAR HYPERTROPHY, Internal medicine, Journal Article, medicine, Mus musculus, Protein binding, Animals, Humans, SCN10A gene, VOLTAGE, Cardiovascular parameters, Heart ventricle hypertrophy, Science & Technology, Human genome, Animal, business.industry, MORTALITY, In vitro study, ta3121, medicine.disease, DYSFUNCTION, 030104 developmental biology, Gene identification, Cardiovascular System & Hematology, Genetic Loci, Heart failure, Expression quantitative trait loci, Genetic association, Meta analysis (topic), Cardiovascular System & Cardiology, Genetic variability, Transcription factor, Myocardial mass, business
Abstract: BACKGROUND Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.OBJECTIVES This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.METHODS We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.RESULTS We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p CONCLUSIONS Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets. (C) 2016 by the American College of Cardiology Foundation.
Published: 2016

9. Seventeen years of statin pharmacogenetics: a systematic review

Author: Anthonius de Boer, Maarten Leusink, N. Charlotte Onland-Moret, Paul I.W. de Bakker, and Anke H. Maitland-van der Zee
Subjects: 0301 basic medicine, Candidate gene, Statin, medicine.drug_class, review, Organic Anion Transporters, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Polymorphism, Single Nucleotide, statins, 03 medical and health sciences, 0302 clinical medicine, Apolipoproteins E, Genetics, Journal Article, Medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Humans, Genetic association, Genetic testing, pharmacogenetics, Pharmacology, biology, medicine.diagnostic_test, business.industry, Liver-Specific Organic Anion Transporter 1, candidate gene studies, Lipoprotein(a), Cholesterol, LDL, Lipid Metabolism, Neoplasm Proteins, Adaptor Proteins, Vesicular Transport, 030104 developmental biology, Cardiovascular Diseases, Genetic Loci, genome-wide association studies, LDL cholesterol, biology.protein, Molecular Medicine, ATP-Binding Cassette Transporters, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, SLCO1B1, Pharmacogenetics, Genome-Wide Association Study
Abstract: Aim: We evaluated the evidence of pharmacogenetic associations with statins in a systematic review. Methods: Two separate outcomes were considered of interest: modification of low-density lipoprotein cholesterol (LDL-C) response and modification of risk for cardiovascular events. Results: In candidate gene studies, 141 loci were claimed to be associated with LDL-C response. Only 5% of these associations were positively replicated. In addition, six genome-wide association studies of LDL-C response identified common SNPs in APOE, LPA, SLCO1B1, SORT1 and ABCG2 at genome-wide significance. None of the investigated SNPs consistently affected the risk reduction for cardiovascular events. Conclusion: Only five genetic loci were consistently associated with LDL-C response. However, as effect sizes are modest, there is no evidence for the value of genetic testing in clinical practice.
Published: 2016

10. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author: Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., 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., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.
Published: 2018

11. Low frequency and rare coding variation contributes to multiple sclerosis risk

Author: Fredrik Karpe, Graeme Stewart, Jan Hillert, Elisabetta Mascia, Matt J. Neville, Verena Grummel, Jonathan L. Haines, Kate Fitzgerald, Bernhard Hemmer, Julia Y Mescheriakova, Benedicte A. Lie, Efthimios Luessi, Federica Esposito, Andreas Ziegler, Ioanna Konidari, Cristin McCabe, Keith R. Edwards, Roland Martin, Daniele Cusi, Elisabeth Gulowsen Celius, Cristina Agliardi, Anne Spurkland, Georgios M. Hadjigeorgiou, Lena Guillot-Noel, Antonios Bayas, Uwe K. Zettl, Kjell-Morten Myhr, Maria Ban, Rogier Q. Hintzen, Frauke Zipp, Mireia Sospedra, Till F. M. Andlauer, Adrian J. Ivinson, Mary F. Davis, Mark Lathrop, Daniela Galimberti, Pierre-Antoine Gourraud, Genevieve Lachance, Bruce A.C. Cree, Robin Lemmens, Ashley Beecham, Steffan D. Bos, Bruce V. Taylor, Maurizio Leone, Manuel Comabella, Maja Jagodic, Helle Bach Søndergaard, David A. Hafler, Ingrid Kockum, Nadia Barizzone, Ralf Gold, Tania Kümpfel, Per Soelberg Sørensen, Seema Kalra, An Goris, Philip Van Damme, Marie B. D'hooghe, Cathy Schaefer, Efthimios Dardiotis, Alastair Compston, Lotti Tajoori, Sandra D'Alfonso, Ilijas Jelcic, Stephen Sawcer, Brigitte Wildemann, Friedemann Paul, Lise Wegner Thoerner, Silvia Delgado, Tomas Olsson, Mitja Mitrovic, Hayrettin Tumani, Henrik Ullum, Lisa F. Barcellos, Xavier Montalban, Ellen Lathi, Finn Sellebjerg, Thomas Werge, Christina M. Lill, Pernilla Stridh, Paul I.W. de Bakker, Cornelia M. van Duijn, Jyoti Khadake, Jac Charlesworth, Melissa Sorosina, Christiane Gasperi, Stephen L. Hauser, Anne H. Cross, Isabelle Cournu-Rebeix, Nikolaos A. Patsopoulos, Fredrik Piehl, Lars Alfredsson, Bertrand Fontaine, Marieme Dembele, Margaret A. Pericak-Vance, Janna Saarela, Ulf Ziemann, Annette Bang Oturai, Stacy J. Caillier, Jorge R. Oksenberg, Bénédicte Dubois, Björn Tackenberg, Christoph Heesen, Jacob L. McCauley, Florian Then Bergh, Clemens Warnke, Sergio E. Baranzini, Peter A. Calabresi, Chris Cotsapas, Clive Hawkins, Martin Stangel, Hakon Hakonarson, Sandra Vukusik, Christiane Graetz, Heinz Wiendl, Howard L. Weiner, Laura Piccio, Giancarlo Comi, Ralf A. Linker, Luisa Bernardinelli, Cristoforo Comi, Filippo Martinelli-Boneschi, Hanne F. Harbo, Dorothea Buck, Clara P. Manrique, David R. Booth, Benjamin Knier, Philip L. De Jager, Viola Pongratz, Laura Ferrè, Vincent Damotte, Adam Santaniello, Theresa Dankowski, and Pirro G. Hysi
Subjects: Genetics, 0303 health sciences, Linkage disequilibrium, Multiple sclerosis, Disease, Biology, Heritability, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Epistasis, Coding region, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common variant signals, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
Published: 2018
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12. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018

13. Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Author: Aaron Isaacs, Sina A. Gharib, Kathleen F. Kerr, Lenore J. Launer, Yuki Bradford, J. Wouter Jukema, Stefan Kääb, Ruth J. F. Loos, Philipp S. Wild, Igor Rudan, Moritz F. Sinner, Annamaria Iorio, David J. Stott, Sheila Ulivi, Martina Müller-Nurasyid, Jerome I. Rotter, Andrew A. Hicks, Leo-Pekka Lyytikäinen, Vilmundur Gudnason, Dan M. Roden, Dana C. Crawford, James F. Wilson, Renate B. Schnabel, Eric Boerwinkle, Mina K. Chung, M. Fabiola Del Greco, Jan A. Kors, Honghuang Lin, Dan E. Arking, Annette Peters, Daniel S. Evans, Kari Stefansson, Francesco Cucca, Harold Snieder, Nona Sotoodehnia, Claudia T. Silva Aldana, Paul I.W. de Bakker, David Schlessinger, Pim van der Harst, Irene Mateo Leach, Kirill V. Tarasov, Marylyn D. Ritchie, Xiaoyan Yin, Marcus Dörr, Jennifer A. Brody, Patrick T. Ellinor, Olli T. Raitakari, Christy L. Avery, Peter W. Macfarlane, Paolo Gasparini, Susan R. Heckbert, John Barnard, Jessica van Setten, Anna F. Dominiczak, Henry Völzke, Edward G. Lakatta, Nilesh J. Samani, Tamara B. Harris, Brenton R. Swenson, Joel S. Bader, Thomas Münzel, Patricia B. Munroe, Hilma Holm, Stefania Bandinelli, Christian Müller, Bruno H. Stricker, Oscar H. Franco, Yongmei Liu, Ivana Kolcic, Peter P. Pramstaller, Josh C. Denny, Maristella Steri, Henry J. Lin, Luigi Ferrucci, Arne Pfeufer, Antonietta Robino, Bruce M. Psaty, Niek Verweij, Lude Franke, Mark Eijgelsheim, Afshin Parsa, Toshiko Tanaka, Folkert W. Asselbergs, Terho Lehtimäki, Stella Trompet, Alvaro Alonso, Harm-Jan Westra, David O. Arnar, Jared W. Magnani, Bouwe P. Krijthe, Cornelia M. van Duijn, Brendan M. Buckley, Jonathan D. Smith, Tim D. Spector, George J. Papanicolaou, Anne M. Butler, Emelia J. Benjamin, Tanja Zeller, Quince Gibson, David R. Van Wagoner, André G. Uitterlinden, Albert V. Smith, Stephan B. Felix, Uwe Völker, Yalda Jamshidi, Ozren Polasek, Daniel F. Gudbjartsson, Harry Campbell, Caroline Hayward, Ilja M. Nolte, Elsayed Z. Soliman, Georg Ehret, Mika Kähönen, Konstantin Strauch, Steven A. Lubitz, Melanie Waldenberger, Alexander Teumer, Sandosh Padmanabhan, Braxton D. Mitchell, Gianfranco Sinagra, Gandin Ilaria, Thomas Meitinger, Marcel den Hoed, Stefan Blankenberg, and J. C. Bis
Subjects: Genetics, QRS complex, Heart block, medicine, cardiovascular system, Missense mutation, Genome-wide association study, Atrial fibrillation, PR interval, Biology, medicine.disease, Genome, Gene
Abstract: Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.
Published: 2018
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14. Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques

Author: Bradford B. Worrall, Gert J. de Borst, Paul I.W. de Bakker, Jessica van Setten, Hassan Foroughi Asl, Gabrielle Paulsson-Berne, Folkert W. den Ruijter, Rainer Malik, Marten A. Siemelink, Gerard Pasterkamp, Johan L.M. Björkegrenn, Sander W. van der Laan, Saskia Haitjema, Folkert W. Asselbergs, Nilesh J. Samani, Martin Dichgans, Ljubica Perisic, Michal Mokry, Heribert Schunkert, Ulf Hedin, Jeanette Erdmann, Surgery, and Cardiology
Subjects: Carotid Artery Diseases, Male, 0301 basic medicine, Vascular wall, Disease, plaque, atherosclerotic, Coronary artery disease, 0302 clinical medicine, cardiovascular disease, Myocardial infarction, Stroke, High Mobility Group Proteins, General Medicine, Middle Aged, stroke, ddc, Cardiovascular Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cardiology, Female, coronary artery disease, medicine.medical_specialty, Genotype, atherosclerotic, Quantitative trait locus, Chronic inflammatory disease, Polymorphism, Single Nucleotide, plaque, 03 medical and health sciences, Internal medicine, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Alleles, Aged, business.industry, genetic loci, Original Articles, medicine.disease, Repressor Proteins, Adaptor Proteins, Vesicular Transport, 030104 developmental biology, Gene Expression Regulation, quantitative trait loci, atherosclerosis, business, 030217 neurology & neurosurgery
Abstract: Supplemental Digital Content is available in the text., Background: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms. Methods: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression. Results: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10−6 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood. Conclusions: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics.
Published: 2018

15. Computational pan-genomics : Status, promises and challenges

Author: Lodewyk F. A. Wessels, Jan O. Korbel, Jasmijn A. Baaijens, Francesca Chiaromonte, Gunnar W. Klau, Kai Ye, Alexander Schönhuth, Francesca D. Ciccarelli, Tobias Marschall, Robin Cijvat, Matthias Schlesner, Adam M. Novak, Eleazar Eskin, Ashley D. Sanders, Sven Rahmann, Carl Shneider, Wigard P. Kloosterman, Knut Reinert, Eric-Wubbo Lameijer, Sandra Smit, Benedict Paten, Mohammed El-Kebir, Valentina Boeva, Evan E. Eichler, Cornelia M. van Duijn, Can Alkan, Jeroen de Ridder, Benjamin Langmead, Dick de Ridder, Jiayin Wang, David Porubsky, Fabio Vandin, Erwin Datema, Ben Raphael, Paul Kersey, Nadia Pisanti, Corinna Ernst, Klaasjan G. Ouwens, Y. Zhang, Thomas Abeel, Erik Garrison, Veli Mäkinen, Paul I.W. de Bakker, Victor Guryev, Siavash Sheikhizadeh, Manja Marz, Marcel Martin, Ole Schulz-Trieglaff, Pieter B. Neerincx, Rayan Chikhi, Eric Rivals, John C. Mu, Raoul J. P. Bonnal, Bas E. Dutilh, Paul Medvedev, Louis Dijkstra, Pierre Peterlongo, Ali Ghaffaari, Daniel Valenzuela, Epidemiology, Gastroenterology & Hepatology, Erasmus MC other, Alkan, Can, Saarland University [Saarbrücken], Max Planck Institute for Informatics [Saarbrücken], Karlsruhe Institute of Technology (KIT), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Delft Bioinformatics Lab [Delft], Delft University of Technology (TU Delft), Computational Science Lab [Amsterdam], University of Amsterdam [Amsterdam] (UvA), Theoretical Biology & Bioinformatics [Utrecht], University Medical Center [Utrecht], Universidade Federal do Rio de Janeiro (UFRJ), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Section genetics [Utrecht], Center for Molecular medicine [Utrecht], University Medical Center [Utrecht]-University Medical Center [Utrecht], Helsinki Institute for Information Technology, Department of Computer Science [Helsinki], Falculty of Science [Helsinki], University of Helsinki-University of Helsinki, Howard Hughes Medical Institute [Santa Cruz] (HHMI), Center for Biomolecular Science & Engineering, European Research Institute for the Biology of Ageing [Groningen] (ERIBA), University Medical Center Groningen [Groningen] (UMCG), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Computer Engineering (Bilkent-CS), Bilkent, Life Sciences [Amsterdam] (MAC4), Centrum Wiskunde & Informatica (CWI), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PSL Research University (PSL), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Department of Statistics [Pennsylvania], Pennsylvania State University (Penn State), Penn State System-Penn State System, Bioinformatics and Sequence Analysis (BONSAI), Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Monet DB Solutions [Amsterdam], KeyGene [Wageningen], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Howard Hughes Medical Institute [Berkeley], University of California [Berkeley], University of California-University of California, Genome Informatics [Duisburg], Universität Duisburg-Essen [Essen], Departement of human genetics [Los Angeles], Computer Science Department [Los Angeles] (UCLA), University of California [Los Angeles] (UCLA), University of California-University of California-University of California [Los Angeles] (UCLA), The Wellcome Trust Sanger Institute [Cambridge], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Universiteit Leiden [Leiden], Department of Computer Science [Baltimore], Johns Hopkins University (JHU), Centre de Physique des Particules de Marseille (CPPM), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Aix Marseille Université (AMU), University of Pennsylvania [Philadelphia], China Agricultural University (CAU), University of Groningen [Groningen], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Dipartimento di Informatica [Pisa] (DI), University of Pisa - Università di Pisa, Faculty of Computer Science [Dortmund], Technische Universität Dortmund [Dortmund] (TU), Service de Pneumologie A [Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Department of Mathematics and Computer Science (Freie Universität Berlin), Freie Universität Berlin, Wageningen University and Research Centre [Wageningen] (WUR), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Division of Theoretical Bioinformatics [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Illumina Cambridge, Illumina, Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Bioinformatics Group [Wageningen], Leiden Observatory [Leiden], Regeneron Pharmaceuticals [Tarrytown], Shaanxi University of Science and Technology, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Universita degli Studi di Padova, The Netherlands Organization for Scientific Research (NWO) Vidi (639.072.309 to A.S., 864.14.004 to B.E.D.), CAPES/BRASIL (to B.E.D.), the Academy of Finland (284598 [CoECGR] to V.M. and D.V.), the Russian Scientific Foundation (14–11–00826 to L.D.), Institut de Biologie Computationnelle (ANR-11-BINF- 0002 to E.R.), and the French Colib’read project (ANR–12– BS02–0008 to E.R.). NSFC 31671372 (to K. Y.), the Dutch Graduate School for Experimental Plant Sciences (054EPS15 to S.S.), the EMGO Institute for Health and Care Research (EMGO+) to K.O., the National Human Genome Research Institute (1U54HG007990 [BD2K] to B.P. and A.M.N., 5U41HG007234 [GENCODE] to B.P.), the W. M. Keck Foundation (DT06172015 to B.P. and A.M.N.), the Simons Foundation (SFLIFE# 351901 to B.P. and A.M.N.), the ARCS Foundation (2014–15 ARCS fellowship to A.M.N.), Edward Schulak (Edward Schulak Fellowship in Genomics to A.M.N.), ANR-11-BINF-0002,IBC,Institut de Biologie Computationnelle de Montpellier(2011), ANR-12-BS02-0008,Colib'read,Méthodes d'extraction d'information biologique dans les données HTS non assemblées(2012), Karlsruhe Institute of Technology ( KIT ), Broad Institute of MIT and Harvard ( BROAD INSTITUTE ), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston] ( MGH ) -Massachusetts Institute of Technology ( MIT ), Delft University of Technology ( TU Delft ), University of Amsterdam [Amsterdam] ( UvA ), Universidade Federal do Rio de Janeiro ( UFRJ ), European Bioinformatics Institute [Hinxton] ( EMBL-EBI ), European Molecular Biology Laboratory [Hinxton], Department of Computer Science, Howard Hughes Medical Institute [Santa Cruz] ( HHMI ), European Research Institute for the Biology of Ageing [Groningen] ( ERIBA ), University Medical Center Groningen [Groningen] ( UMCG ), Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Méthodes et Algorithmes pour la Bioinformatique ( MAB ), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier ( LIRMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Engineering ( Bilkent-CS ), Life Sciences [Amsterdam] ( MAC4 ), Centrum Wiskunde & Informatica ( CWI ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), PSL Research University ( PSL ), Centre de Bioinformatique ( CBIO ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Istituto Nazionale Genetica Molecolare [Milano] ( INGM ), PennState University [Pennsylvania] ( PSU ), Bioinformatics and Sequence Analysis ( BONSAI ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 ( CRIStAL ), Ecole Centrale de Lille-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut Mines-Télécom [Paris]-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Lille-Institut Mines-Télécom [Paris]-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ), Erasmus University Medical Center [Rotterdam], Computer Science Department [Los Angeles] ( UCLA ), University of California at Los Angeles [Los Angeles] ( UCLA ) -University of California at Los Angeles [Los Angeles] ( UCLA ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Johns Hopkins University ( JHU ), Centre de Physique des Particules de Marseille ( CPPM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Aix Marseille Université ( AMU ), China Agricultural University ( CAU ), Vrije Universiteit Amsterdam [Amsterdam] ( VU ), Scalable, Optimized and Parallel Algorithms for Genomics ( GenScale ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -GESTION DES DONNÉES ET DE LA CONNAISSANCE ( IRISA_D7 ), Institut de Recherche en Informatique et Systèmes Aléatoires ( IRISA ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -Université de Bretagne Sud ( UBS ) -École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ) -IMT Atlantique Bretagne-Pays de la Loire ( IMT Atlantique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -Université de Bretagne Sud ( UBS ) -École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ) -IMT Atlantique Bretagne-Pays de la Loire ( IMT Atlantique ) -Institut de Recherche en Informatique et Systèmes Aléatoires ( IRISA ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -Université de Bretagne Sud ( UBS ) -École normale supérieure - Rennes ( ENS Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ) -IMT Atlantique Bretagne-Pays de la Loire ( IMT Atlantique ), Dipartimento di Informatica [Pisa] ( DI ), University of Pisa [Pisa], Technische Universität Dortmund [Dortmund] ( TU ), Department of Mathematics and Computer Science ( Freie Universität Berlin ), Freie Universität Berlin [Berlin], Wageningen University and Research Centre [Wageningen] ( WUR ), K.U.Leuven, German Cancer Research Center [Heidelberg] ( DKFZ ), Helmholtz-Gemeinschaft-Helmholtz-Gemeinschaft, BC Cancer Agency ( BCCRC ) -British Columbia Cancer Agency Research Centre, Netherlands Cancer Institute ( NKI ), ANR-11-BINF-0002,IBC,Institut de Biologie Computationnelle de Montpellier ( 2011 ), ANR-12-BS02-0008,Colib'read,Méthodes d'extraction d'information biologique dans les données HTS non assemblées ( 2012 ), Helsinki Institute for Information Technology (HIIT), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Aalto University, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Bilkent University [Ankara], Université Paris sciences et lettres (PSL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Statistics [PennState], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Howard Hughes Medical Institute (HHMI), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Universiteit Leiden, Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Mathematics and Computer Science, Wageningen University and Research [Wageningen] (WUR), Università degli Studi di Padova = University of Padua (Unipd), ANR-11-BINF-0002,IBC,Institut de biologie Computationnelle(2011), Aalto University-University of Helsinki, University of California [Santa Cruz] (UCSC), University of California, Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Université de Lille-Centrale Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centrale Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: 0301 basic medicine, Data structures, Computer science, Medizin, 02 engineering and technology, computer.software_genre, Genome, Computational and Statistical Genetics, data structures, haplotypes, pan-genome, read mapping, sequence graph, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], 0303 health sciences, education.field_of_study, Point (typography), Genomics, Papers, Data mining, Sequence graph, Computational problem, Construct (philosophy), Algorithms, Human, Information Systems, Bioinformatics, 0206 medical engineering, Population, Pan-genome, 03 medical and health sciences, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Bioinformatica, Humans, Haplotypes, Read mapping, Computational Biology, Genome, Human, Software, Molecular Biology, education, Representation (mathematics), 030304 developmental biology, Computational genomics, Data structure, Data science, Human genetics, 030104 developmental biology, Paradigm shift, ddc:004, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], EPS, computer, 020602 bioinformatics
Abstract: Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case ofHomo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic datasets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension ofcomputational pan-genomics, a new sub-area of research in computational biology. In this paper, we generalize existing definitions and understand apan-genomeas any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies, and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.
Published: 2018

16. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk

Author: John A. Todd, Tobias L. Lenz, Soumya Raychaudhuri, Joanna M. M. Howson, Xinli Hu, Aaron J. Deutsch, Buhm Han, Paul I.W. de Bakker, Wei-Min Chen, Stephen S. Rich, Suna Onengut-Gumuscu, Howson, Joanna [0000-0001-7618-0050], and Apollo - University of Cambridge Repository
Subjects: Male, Linkage disequilibrium, Genotype, Locus (genetics), Human leukocyte antigen, Biology, Research Support, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, HLA-DQ alpha-Chains, N.I.H, Genetic, Research Support, N.I.H., Extramural, Models, Risk Factors, HLA-DQ, Diabetes Mellitus, Journal Article, Genetics, HLA-DR, HLA-DQ beta-Chains, Humans, Polymorphism, Amino Acids, Non-U.S. Gov't, chemistry.chemical_classification, Models, Genetic, Research Support, Non-U.S. Gov't, Extramural, Epistasis, Genetic, Single Nucleotide, Explained variation, Amino acid, Diabetes Mellitus, Type 1, Logistic Models, Phenotype, Haplotypes, chemistry, Case-Control Studies, Epistasis, biology.protein, Female, Algorithms, Type 1, HLA-DRB1 Chains
Abstract: Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10(-721)) and 71 (P = 1 × 10(-95)) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1-HLA-DQA1-HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1-HLA-DQA1-HLA-DQB1 haplotypes (P = 1.6 × 10(-64)). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.
Published: 2015

17. Erratum

Author: Deepali Jaju, Melanie Neijts, Gabrielle Boucher, Arpi Minassian, James D. Stewart, Andreas Voss, Pim van der Harst, Duanping Liao, Joshua C. Bis, Kari E. North, Matteo Barcella, Michel G. Nivard, Jitender Kumar, Andrew Wong, Dewleen G. Baker, G. Ehret, Sulayma Albarwani, Kathleen F. Kerr, Quenna Wong, Ville Huikari, Alexander Kluttig, Andrew P. Morris, Eco J. C. de Geus, Albertine J. Oldehinkel, Ann-Christine Syvänen, Martina Mueller-Nurasyid, Yong Li, Marcel den Hoed, Henning Tiemeier, Henriette E. Meyer zu Schwabedissen, Dorret I. Boomsma, Joop D. Lefrandt, Mohammad Hadi Zafarmand, Victoria B. Risbrough, Halina Greiser, Bruce M. Psaty, Oscar H. Franco, Niek Verweij, Cees A. Swenne, Antti M. Kiviniemi, Konstantin Strauch, Markus Juonala, Zhu Ming Zhang, Nicholas L. Smith, Olli T. Raitakari, Daiane Hemerich, Daniel T. O'Connor, Christopher J. O'Donnell, Riad Bayoumi, Peter Friberg, Alvaro Alonso, Julian F. Thayer, Caroline M. Nievergelt, Delilah Zabaneh, Steven A. Lubitz, Tomas Axelsson, Terho Lehtimäki, Daniele Cusi, Eric A. Whitsel, Arie M. van Roon, Kjell Nikus, Bruno H. Stricker, Bouwe P. Krijthe, Stefan Kääb, Lars Lind, Abdel Abdellaoui, Timothy A. Thornton, Anubha Mahajan, Johan Sundström, Nona Sotoodehnia, Charles Kooperberg, Moritz F. Sinner, Leo-Pekka Lyytikäinen, Xavier Jouven, Tanja G. M. Vrijkotte, Sander W. van der Laan, Tatiana Kuznetsova, Patrick T. Ellinor, Alexander P. Reiner, Ilja M. Nolte, Marian C. Limacher, Paul I.W. de Bakker, Ahmad Vaez, Albert Hofman, Meena Kumari, Folkert W. Asselbergs, Juhani Junttila, Bram Dierckx, Marjo-Riitta Järvelin, Ingrid E. Christophersen, Annie Britton, Cathy C. Laurie, Phyllis K. Stein, Katarzyna Stolarz-Skrzypek, Juha Auvinen, Alexander Teumer, Vilmantas Giedraitis, Foram N. Ashar, Jenny van Dongen, David S. Siscovick, Markku Eskola, Jussi Hernesniemi, Janine F. Felix, M. Loretto Munoz, Jessica van Setten, Yun Li, Bianca J. J. M. Brundel, Christine M. Albert, Annette Peters, Jerome I. Rotter, Nina Hutri-Kähönen, Mark A. Geyer, Lesley E. Tinker, Vinicius Tragante, Susan R. Heckbert, Alan B. Zonderman, John D. Rioux, Kent D. Taylor, Shih-Jen Hwang, Johan Ormel, Mike A. Nalls, Erik Ingelsson, Kirk C. Wilhelmsen, John S. Floras, Diana Kuh, Elsayed Z. Soliman, Henry J. Lin, Brenda W.J.H. Penninx, Mika Kivimäki, Maaike G. J. Gademan, Jouke-Jan Hottenga, Mika Kähönen, Gerjan Navis, Siegfried Perz, Tamar Sofer, Catharina A. Hartman, Barbara McKnight, Jan A. Kors, Rick Jansen, Melanie Waldenberger, Nina Mononen, Heikki V. Huikuri, Azmeraw T. Amare, Mohammad L. Hassan, Jan A. Staessen, Adam X. Maihofer, Erika Salvi, Rob J. Bieringa, Benedikt von der Heyde, Andrea Dietrich, Peter J. van der Most, Philippe Goyette, Harriëtte Riese, Michele K. Evans, Stephanie M. Gogarten, Jean-Claude Tardif, Harold Snieder, Adrienne M. Stilp, Christy L. Avery, Johannes H. Smit, Gonneke Willemsen, Yuri Milaneschi, André G. Uitterlinden, Cecilia M. Lindgren, VU University medical center, APH - Mental Health, Psychiatry, Physiology, ACS - Heart failure & arrhythmias, APH - Methodology, and APH - Digital Health
Subjects: 0301 basic medicine, Genetics, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Disease risk, Heart rate variability, 030217 neurology & neurosurgery
Abstract: Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.
Published: 2017

18. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author: Gerjan Navis, Moritz F. Sinner, Kathleen F. Kerr, Heikki V. Huikuri, Daniele Cusi, Oscar H. Franco, Marian C. Limacher, Charles Kooperberg, Gabrielle Boucher, Riad Bayoumi, Juhani Junttila, Ann-Christine Syvänen, Andrew P. Morris, Anubha Mahajan, Andreas Voss, Paul I.W. de Bakker, Patrick T. Ellinor, Phyllis K. Stein, Janine F. Felix, Mark A. Geyer, Mike A. Nalls, Erik Ingelsson, Vinicius Tragante, Joshua C. Bis, Kari E. North, Jean-Claude Tardif, Harold Snieder, Azmeraw T. Amare, Katarzyna Stolarz-Skrzypek, Markku Eskola, Ilja M. Nolte, Tanja G. M. Vrijkotte, Elsayed Z. Soliman, Deepali Jaju, Melanie Neijts, Adrienne M. Stilp, Mika Kähönen, Henry J. Lin, Jessica van Setten, Meena Kumari, Halina Greiser, John S. Floras, Henriette E. Meyer zu Schwabedissen, Mohammad Hadi Zafarmand, Dewleen G. Baker, Rick Jansen, Cathy C. Laurie, Matteo Barcella, Christy L. Avery, Stefan Kääb, Michel G. Nivard, Jitender Kumar, Lars Lind, Alexander Teumer, Johan Sundström, Kirk C. Wilhelmsen, Barbara McKnight, Vilmantas Giedraitis, Johannes H. Smit, Gonneke Willemsen, Nona Sotoodehnia, Michele K. Evans, Christine M. Albert, Kent D. Taylor, Marcel den Hoed, James D. Stewart, Peter Friberg, Alvaro Alonso, Susan R. Heckbert, Kjell Nikus, Siegfried Perz, André G. Uitterlinden, Bruce M. Psaty, Antti M. Kiviniemi, G. Ehret, Jouke-Jan Hottenga, Sulayma Albarwani, Bouwe P. Krijthe, Timothy A. Thornton, Caroline M. Nievergelt, Delilah Zabaneh, Zhu Ming Zhang, Annie Britton, Ingrid E. Christophersen, Adam X. Maihofer, Juha Auvinen, David S. Siscovick, Arie M. van Roon, Xavier Jouven, Stephanie M. Gogarten, M. Loretto Munoz, Erika Salvi, Folkert W. Asselbergs, Bram Dierckx, Marjo-Riitta Järvelin, Cecilia M. Lindgren, Yun Li, Quenna Wong, Alan B. Zonderman, Yuri Milaneschi, John D. Rioux, Brenda W.J.H. Penninx, Philippe Goyette, Niek Verweij, Harriëtte Riese, Bruno H. Stricker, Markus Juonala, Rob J. Bieringa, Arpi Minassian, Jenny van Dongen, Abdel Abdellaoui, Foram N. Ashar, Jan A. Kors, Albertine J. Oldehinkel, Jussi Hernesniemi, Sander W. van der Laan, Ahmad Vaez, Nina Hutri-Kähönen, Annette Peters, Lesley E. Tinker, Albert Hofman, Dorret I. Boomsma, Victoria B. Risbrough, Tamar Sofer, Pim van der Harst, Konstantin Strauch, Steven A. Lubitz, Catharina A. Hartman, Jerome I. Rotter, Shih-Jen Hwang, Duanping Liao, Mika Kivimäki, Mohammad L. Hassan, Andrew Wong, Peter J. van der Most, Alexander Kluttig, Nina Mononen, Eco J. C. de Geus, Henning Tiemeier, Benedikt von der Heyde, Martina Müller-Nurasyid, Joop D. Lefrandt, Andrea Dietrich, Nicholas L. Smith, Terho Lehtimäki, Bianca J. J. M. Brundel, Jan A. Staessen, Cees A. Swenne, Julian F. Thayer, Daniel T. O'Connor, Christopher J. O'Donnell, Eric A. Whitsel, Tatiana Kuznetsova, Alexander P. Reiner, Johan Ormel, Ville Huikari, Yong Li, Tomas Axelsson, Olli T. Raitakari, Daiane Hemerich, Leo-Pekka Lyytikäinen, Maaike G. J. Gademan, Melanie Waldenberger, Diana Kuh, Ehret, Georg Benedikt, APH - Personalized Medicine, APH - Global Health, Other Research, ACS - Amsterdam Cardiovascular Sciences, Public and occupational health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, ARD - Amsterdam Reproduction and Development, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Physiology, ACS - Heart failure & arrhythmias, APH - Digital Health, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Value, Affordability and Sustainability (VALUE), Biological Psychology, Praxis, Environmental Geography (former), Child and Adolescent Psychiatry / Psychology, Rheumatology, Epidemiology, Medical Informatics, and Internal Medicine
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, Potassium Channels, Chemistry(all), Muscle Proteins, General Physics and Astronomy, Genome-wide association study, Blood Pressure, PEDIGREES, Bioinformatics, Biochemistry, Genome-wide association studies, Medical and Health Sciences, Cohort Studies, Heart Rate, Risk Factors, RGS Proteins/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, RECORDINGS, Heart rate variability, Vagal tone, European Continental Ancestry Group/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics, ddc:616, Muscle Proteins/genetics, Multidisciplinary, digestive, oral, and skin physiology, Single Nucleotide, Multidisciplinary Sciences, Science & Technology - Other Topics, Heart Diseases/genetics/physiopathology, Erratum, circulatory and respiratory physiology, Heart Diseases, Science, Quantitative Trait Loci, RESPIRATORY SINUS ARRHYTHMIA, Quantitative trait locus, Biology, Physics and Astronomy(all), Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Article, PARASYMPATHETIC REGULATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Heart rate, Journal Article, Humans, Genetic Predisposition to Disease, COHORT, Polymorphism, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, MODULATOR, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), MORTALITY, Cardiovascular genetics, General Chemistry, Membrane hyperpolarization, ta3121, 030104 developmental biology, Expression quantitative trait loci, ATRIAL-FIBRILLATION, Potassium Channels/genetics, RGS Proteins, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract: Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74, Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.
Published: 2017

19. Negative selection in humans and fruit flies involves synergistic epistasis

Author: Sara L. Pulit, Jan H. Veldink, Olga A. Vakhrusheva, Georgii A. Bazykin, Paul I.W. de Bakker, Jae Hoon Sul, Alzheimer’s Disease Neuroimaging Initiative, Shamil R. Sunyaev, Alexey S. Kondrashov, Leonard H. van den Berg, Mashaal Sohail, Laurent C. Francioli, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, and APH - Methodology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Linkage disequilibrium, Genome, Insect, Mutation, Missense, Research Support, Genome, Article, Linkage Disequilibrium, N.I.H, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Mutation Rate, Research Support, N.I.H., Extramural, Journal Article, Animals, Humans, Selection, Genetic, Allele, Non-U.S. Gov't, Alleles, Selection (genetic algorithm), 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Natural selection, biology, Genome, Human, Research Support, Non-U.S. Gov't, Extramural, Epistasis, Genetic, biology.organism_classification, Drosophila melanogaster, 030104 developmental biology, Mutation (genetic algorithm), Epistasis, Genetic Fitness, 030217 neurology & neurosurgery
Abstract: Negative selection against deleterious alleles produced by mutation is the most common form of natural selection, which strongly influences within-population variation and interspecific divergence. However, some fundamental properties of negative selection remain obscure. In particular, it is still not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis must produce negative linkage disequilibrium between deleterious alleles, and therefore, underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function (LoF) alleles in eight independent datasets from modern human andDrosophila melanogasterpopulations. Thus, ongoing selection against deleterious alleles is characterized by synergistic epistasis, which can explain how human and fly populations persist despite very high genomic deleterious mutation rates.
Published: 2017

20. A framework for the detection of de novo mutations in family-based sequencing data

Author: Mark A. DePristo, Kiran V. Garimella, Eric Banks, Mark J. Daly, Mircea Cretu-Stancu, Laurent C. Francioli, Paul I.W. de Bakker, Kaitlin E. Samocha, Benjamin M. Neale, Wigard P. Kloosterman, Menachem Fromer, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Genome of the Netherlands consortium, and including
Subjects: Adult, Male, 0301 basic medicine, Netherlands Twin Register (NTR), Mutation rate, Genotype, Posterior probability, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome, Article, 03 medical and health sciences, Germline mutation, Genetics, Journal Article, Humans, Exome, Genetics(clinical), Child, Indel, Germ-Line Mutation, Genetics (clinical), Chromosomes, Human, X, Models, Genetic, Sequence Analysis, DNA, Human genetics, Pedigree, 030104 developmental biology, Female, Software, Genome-Wide Association Study
Abstract: Germline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single nucleotide variants and short insertions and deletions (indels) from sequence data collected in parent-offspring trios. We compute the joint probability of the data given the genotype likelihoods in the individual family members, the known familial relationships and a prior probability for the mutation rate. Candidate de novo mutations (DNMs) are reported along with their posterior probability, providing a systematic way to prioritize them for validation. Our tool is integrated in the Genome Analysis Toolkit and can be used together with the ReadBackedPhasing module to infer the parental origin of DNMs based on phase-informative reads. Using simulated data, we show that PBT outperforms existing tools, especially in low coverage data and on the X chromosome. We further show that PBT displays high validation rates on empirical parent-offspring sequencing data for whole-exome data from 104 trios and X-chromosome data from 249 parent-offspring families. Finally, we demonstrate an association between father’s age at conception and the number of DNMs in female offspring’s X chromosome, consistent with previous literature reports.European Journal of Human Genetics advance online publication, 23 November 2016; doi:10.1038/ejhg.2016.147.
Published: 2017

21. Genetic variants associated with type 2 diabetes and adiposity and risk of intracranial and abdominal aortic aneurysms

Author: Arno de Wilde, Ynte M. Ruigrok, Albert Hofman, André G. Uitterlinden, Julien Vaucher, Femke N G van 't Hof, Paul I.W. de Bakker, Lambertus A. Kiemeney, Michael V. Holmes, Gabriel J.E. Rinkel, Jan D. Blankensteijn, Fernando Rivadeneira, Sita H. Vermeulen, Annette F. Baas, Epidemiology, Internal Medicine, Surgery, ACS - Atherosclerosis & ischemic syndromes, and ACS - Microcirculation
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Type 2 diabetes, Logistic regression, Research Support, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Aneurysm, SDG 3 - Good Health and Well-being, Internal medicine, Epidemiology, Mendelian randomization, medicine, Diabetes Mellitus, Journal Article, Genetics, Humans, Abdominal, Genetics(clinical), Genetic Predisposition to Disease, cardiovascular diseases, Risk factor, Polymorphism, Non-U.S. Gov't, Genetics (clinical), Adiposity, Aged, business.industry, Research Support, Non-U.S. Gov't, Intracranial Aneurysm, Single Nucleotide, Middle Aged, medicine.disease, Aortic Aneurysm, 030104 developmental biology, Quartile, Diabetes Mellitus, Type 2, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], cardiovascular system, Female, business, Body mass index, Type 2, Aortic Aneurysm, Abdominal
Abstract: Epidemiological studies show that type 2 diabetes (T2D) is inversely associated with intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA). Although adiposity has not been considered a risk factor for IA, there have been inconsistent reports relating adiposity to AAA risk. We assessed whether these observations have a genetic, causal basis. To this end, we extracted genotypes of validated single-nucleotide polymorphisms associated with T2D (n=65), body mass index (BMI) (n=97) and waist–hip ratio adjusted for BMI (WHRadjBMI) (n=47) from genotype data collected in 717 IA cases and 1988 controls, and in 818 AAA cases and 3004 controls, all of Dutch descent. For each of these three traits, we computed genetic risk scores (GRS) for each individual in these case–control data sets by summing the number of risk alleles weighted by their published effect size, and tested whether these GRS were associated with risk of aneurysm. We divided the cohorts into GRS quartiles, and compared IA and AAA risk in the highest with the lowest GRS quartile using logistic regression. We found no evidence for association in IA or AAA risk between top and bottom quartiles for the genetic risk scores for T2D, BMI and WHRadjBMI. However, additional Mendelian randomization analyses suggested a trend to potentially causal associations between BMI and WHRadjBMI and risk of AAA. Overall, our results do not support epidemiological observations relating T2D to aneurysm risk, but may indicate a potential role of adiposity in AAA that requires further investigation.European Journal of Human Genetics advance online publication, 5 April 2017; doi:10.1038/ejhg.2017.48.
Published: 2017

22. No association between CYP3A4*22 and statin effectiveness in reducing the risk for myocardial infarction

Author: Loes E. Visser, Catherine E. de Keyser, Bruno H. Stricker, Ron H.N. van Schaik, Anthonius de Boer, Maarten Leusink, Anke-Hilse Maitland-van der Zee, Paul I.W. de Bakker, N. Charlotte Onland-Moret, Albert Hofman, Erasmus MC other, Epidemiology, Internal Medicine, and Clinical Chemistry
Subjects: Male, Risk, Oncology, medicine.medical_specialty, Statin, Genotype, medicine.drug_class, Myocardial Infarction, Rotterdam Study, Internal medicine, Genetics, medicine, Cytochrome P-450 CYP3A, Humans, cardiovascular diseases, Myocardial infarction, Allele, Alleles, Aged, Pharmacology, Proportional hazards model, business.industry, Genetic Variation, Odds ratio, Middle Aged, medicine.disease, Minor allele frequency, Endocrinology, Pharmacogenetics, Case-Control Studies, Molecular Medicine, Female, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract: Aim: Genetic variation has been shown to influence statin response in terms of lowering LDL cholesterol. The recently discovered CYP3A4*22 allele (defined as rs35599367) has been shown to affect statin-induced LDL cholesterol lowering. Our objective was to investigate whether this polymorphism modifies the risk reduction for myocardial infarction (MI) by statins. Patients & methods: We analyzed the interaction between the *22 minor allele and statin use in the independent Utrecht Cardiovascular Pharmacogenetics study and Rotterdam Study, using logistic and Cox regression models. Results: In total, 771 MI cases and 6131 controls were included in the analyses. There was no effect of the CYP3A4*22 allelic status in the studies separately, nor when the estimates from both studies were combined (interaction odds ratio: 1.27; 95% CI: 0.73–2.21; p = 0.40 for carriers of the minor T-allele). Conclusion: We found no association of the CYP3A4*22 minor allele (rs35599367) with the effectiveness of statins in reducing MI risk. Original submitted 9 April 2014; Revision submitted 30 May 2014
Published: 2014

23. Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes

Author: Michael Weichenthal, Soumya Raychaudhuri, Anne M. Bowcock, Yukinori Okada, Peter K. Gregersen, Trilokraj Tejasvi, Philip E. Stuart, John J. Voorhees, Andre Franke, Vinod Chandran, Fawnda Pellett, Dafna D. Gladman, James T. Elder, Lam C. Tsoi, Proton Rahman, Paul I.W. de Bakker, Eva Ellinghaus, Buhm Han, Gonçalo R. Abecasis, Remy A. Pollock, Rajan P. Nair, and Gerald G. Krueger
Subjects: Genotype, genetic structures, Locus (genetics), HLA-C Antigens, Human leukocyte antigen, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, Major Histocompatibility Complex, Genetics, Humans, Psoriasis, SNP, Genetics(clinical), Genetic Predisposition to Disease, Amino Acid Sequence, Gene, Peptide sequence, Genetic Association Studies, Genetics (clinical), chemistry.chemical_classification, Base Sequence, Arthritis, Psoriatic, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Chromosome Mapping, Amino acid, chemistry, HLA-B Antigens, Immunology, biology.protein, circulatory and respiratory physiology
Abstract: Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.
Published: 2014

24. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author: Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics
Subjects: Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
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 similar to 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

25. Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Author: Sefanja Achterberg, Matthew Traylor, Agniesczka Slowik, Steven J. Kittner, Gudmar Thorleifsson, Steve Bevan, Rainer Malik, Robert Clarke, Martin Farrall, Michèle M. Sale, Jemma C. Hopewell, Martin Dichgans, Lars Rönnblom, Giorgio B. Boncoraglio, M. Arfan Ikram, Myriam Fornage, Johanna K. Sandling, Andre Franke, Sudha Seshadri, Björn M. Hansen, Bradford B. Worrall, Christopher Levi, Bo Norrving, Joshua C. Bis, Bruce M. Psaty, Pankaj Sharma, An Goris, Hugh S. Markus, Peter M. Rothwell, Cathie Sudlow, Guillame Pare, Arne Lindgren, James F. Meschia, Jonathan Rosand, Laura L. Kilarski, Paul I.W. de Bakker, Vincent Thijs, Joan Montaner, William J. Devan, Kari Stefanson, Cisca Wijmenga, L. Jaap Kappelle, Elizabeth G. Holliday, Braxton D. Mitchell, Unnar Thorsteinsdottir, Ale Algra, Matthew Walters, Solveig Gretarsdottir, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Risk, medicine.medical_specialty, Neurology, Genotype, INTRACEREBRAL HEMORRHAGE, LOCI, RATIONALE, Single-nucleotide polymorphism, Genome-wide association study, VARIANTS, Bioinformatics, Polymorphism, Single Nucleotide, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, DESIGN, Internal medicine, IMPUTATION, Humans, Medicine, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Cerebral Hemorrhage, 030304 developmental biology, Intracerebral hemorrhage, 0303 health sciences, Chromosomes, Human, Pair 12, business.industry, Odds ratio, ALLELES, medicine.disease, 3. Good health, Stroke, C431 Medical Genetics, Meta-analysis, RISK-FACTORS, Cardiology, Neurology (clinical), BURDEN, business, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract: Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico “look-up” of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07–1.13], p = 7.12 × 10−11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90–1.17], p = 0.695). Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
Published: 2014

26. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

Author: Luigi Laghi, Jens U. Marquardt, Lude Franke, Harm-Jan Westra, Ralf Kiesslich, Cisca Wijmenga, Julio Perez de la Serna, Rosario Cuomo, Jan Tack, Peter R. Galle, Ines Gockel, Henning G. Schulz, Giovanni Sarnelli, Daniel Drescher, Jessica Becker, Stefan Niebisch, Elisabeth Mangold, Anna Latiano, Paul I.W. de Bakker, V. Annese, Uberto Fumagalli, Antonio Ruiz de León, Michael T. Heneka, Alexander J. Eckardt, Per Hoffmann, Mira M. Wouters, Hans Dieter Allescher, Julian Zimmermann, Timo Hess, Werner Kneist, Elena Urcelay, Ana G. Vigo, Hauke Lang, Markus M. Nöthen, Gosia Trynka, Henning R. Gockel, Burkhard H.A. von Rahden, Vinod Kumar, Karl-Peter Hopfner, David Ramonet, Stefan Herms, Stefanie Heilmann, Michael Knapp, Michaela Müller, Guy E. Boeckxstaens, Johannes Schumacher, Manuel Mattheisen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Ines, Gockel, Jessica, Becker, Mira M., Wouter, Stefan, Niebisch, Henning R., Gockel, Timo, He, David, Ramonet, Julian, Zimmermann, Ana Gonz?lez, Vigo, Gosia, Trynka, Antonio Ruiz de, Le?n, Julio P?rez de la, Serna, Elena, Urcelay, Vinod, Kumar, Lude, Franke, Harm Jan, Westra, Daniel, Drescher, Werner, Kneist, Jens U., Marquardt, Peter R., Galle, Manuel, Mattheisen, Vito, Annese, Anna, Latiano, Uberto, Fumagalli, Luigi, Laghi, Cuomo, Rosario, Sarnelli, Giovanni, Michaela, M?ller, Alexander J., Eckardt, Jan, Tack, Per, Hoffmann, Stefan, Herm, Elisabeth, Mangold, Stefanie, Heilmann, Ralf, Kiesslich, Burkhard H. A., von Rahden, Hans Dieter, Allescher, Henning G., Schulz, Cisca, Wijmenga, Michael T., Heneka, Hauke, Lang, Karl Peter, Hopfner, Markus M., N?then, Guy E., Boeckxstaen, Paul I. W., de Bakker, Michael, Knapp, and Johannes, Schumacher
Subjects: Male, Models, Molecular, Achalasia, Immunogenetics, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, digestive system, HLA-DQ alpha-Chains, HLA-DQ Antigens, HLA-DQ, otorhinolaryngologic diseases, Genetics, medicine, HLA-DQ beta-Chains, Humans, Genetic Predisposition to Disease, Esophagus, Alleles, Genetic Association Studies, Genetic association, Motility disorder, ASSOCIATION, medicine.disease, digestive system diseases, Esophageal Achalasia, INSIGHTS, Logistic Models, medicine.anatomical_structure, Amino Acid Substitution, Haplotypes, Case-Control Studies, Immunology, biology.protein, Female, Idiopathic achalasia, genetic, MHC
Abstract: Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular domain of HLA-DQ alpha 1 at position 41 (lysine encoded by HLA-DQA1*01:03; P = 5.60 x 10(-10)) and of HLA-DQ beta 1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P = 1.20 x 10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
Published: 2014

27. C9orf72andUNC13Aare shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis

Author: Max Koppers, Jochen H. Weishaupt, Philip Van Damme, Aleksey Shatunov, Albert C. Ludolph, John Landers, Karen E. Morrison, Jan H. Veldink, R. Jeroen Pasterkamp, Orla Hardiman, Judith Melki, Karol Estrada, David Czell, Robert H. Brown, John C. van Swieten, Fernando Rivadeneira, Vincent Meininger, P. Nigel Leigh, Leonard H. van den Berg, Wim Robberecht, Peter M. Andersen, Vivianna M. Van Deerlin, Albert Hofman, Christopher Shaw, André G. Uitterlinden, Vincenzo Silani, Michael A. van Es, Frank P. Diekstra, Adriano Chiò, Isabella Fogh, Peter Heutink, Markus Weber, Paul I.W. de Bakker, Pamela J. Shaw, Ammar Al-Chalabi, and Bryan J. Traynor
Subjects: Genetics, nutritional and metabolic diseases, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, medicine.disease, nervous system diseases, Neurology, C9orf72, mental disorders, Genotype, medicine, Neurology (clinical), Amyotrophic lateral sclerosis, Frontotemporal dementia, Genetic association
Abstract: OBJECTIVE Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. METHODS We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. RESULTS Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10(-12) ) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10(-11) ) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10(-7) ) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10(-7) ). INTERPRETATION We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.
Published: 2014

28. Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Author: Daniel L. Kastner, Elaine F. Remmers, Ahmet Gül, Paul I.W. de Bakker, Yohei Kirino, and Michael J. Ombrello
Subjects: Signal peptide, Linkage disequilibrium, Genotype, Antigen presentation, Genes, MHC Class I, Immunoglobulins, Peptide binding, Single-nucleotide polymorphism, Human leukocyte antigen, Protein Sorting Signals, Major histocompatibility complex, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Risk Factors, Commentaries, MHC class I, Odds Ratio, Humans, Genetic Predisposition to Disease, Alleles, Genetics, Multidisciplinary, biology, Behcet Syndrome, Histocompatibility Antigens Class I, Molecular biology, Logistic Models, Haplotypes, Multivariate Analysis, HLA-B51 Antigen, biology.protein
Abstract: The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behcet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10(-8)). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-I-killer immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.
Published: 2014

29. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations

Author: Seok Hwee Koo, Edmund J.D. Lee, Yukinori Okada, Yik-Ying Teo, Wei-Yen Lim, Richie Soong, Francis A. Plummer, Nisha Esakimuthu Pillai, Wenting Xu, Kee Seng Chia, Ma Luo, Linda Wei Lin Tan, Peter Little, Koon Yong Tay, Wan Ting Poh, Paul I.W. de Bakker, Soumya Raychaudhuri, Mohammad Ali, Thomas Bielawny, Xu Wang, Markus R. Wenk, Rick Twee-Hee Ong, Erwin Tantoso, Woei-Yuh Saw, and Trevor Peterson
Subjects: Genetics, education.field_of_study, Linkage disequilibrium, Population, Single-nucleotide polymorphism, General Medicine, Human leukocyte antigen, HLA-DP alpha-Chains, Biology, Southeast asian, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Asian People, Genetic Loci, HLA Antigens, Humans, International HapMap Project, education, Molecular Biology, Genotyping, Alleles, HLA-DP beta-Chains, Genetics (clinical), Imputation (genetics)
Abstract: The major histocompatibility complex (MHC) containing the classical human leukocyte antigen (HLA) Class I and Class II genes is among the most polymorphic and diverse regions in the human genome. Despite the clinical importance of identifying the HLA types, very few databases jointly characterize densely genotyped single nucleotide polymorphisms (SNPs) and HLA alleles in the same samples. To date, the HapMap presents the only public resource that provides a SNP reference panel for predicting HLA alleles, constructed with four collections of individuals of north-western European, northern Han Chinese, cosmopolitan Japanese and Yoruba Nigerian ancestry. Owing to complex patterns of linkage disequilibrium in this region, it is unclear whether the HapMap reference panels can be appropriately utilized for other populations. Here, we describe a public resource for the Singapore Genome Variation Project with: (i) dense genotyping across ∼ 9000 SNPs in the MHC; (ii) four-digit HLA typing for eight Class I and Class II loci, in 96 southern Han Chinese, 89 Southeast Asian Malays and 83 Tamil Indians. This resource provides population estimates of the frequencies of HLA alleles at these eight loci in the three population groups, particularly for HLA-DPA1 and HLA-DPB1 that were not assayed in HapMap. Comparing between population-specific reference panels and a cosmopolitan panel created from all four HapMap populations, we demonstrate that more accurate imputation is obtained with population-specific panels than with the cosmopolitan panel, especially for the Malays and Indians but even when imputing between northern and southern Han Chinese. As with SNP imputation, common HLA alleles were imputed with greater accuracy than low-frequency variants.
Published: 2014

30. Association Claims in the Sequencing Era

Author: Sara L. Pulit, Maarten Leusink, Paul I.W. de Bakker, and Androniki Menelaou
Subjects: bias, History, lcsh:QH426-470, Association (object-oriented programming), Sequencing data, association, Genome-wide association study, Review, significance, Scientific literature, Bioinformatics, Data science, Human genetics, DNA sequencing, complex traits, lcsh:Genetics, Genetics, GWAS, next-generation sequencing, Human genome, Genetics (clinical), Genetic association
Abstract: Since the completion of the Human Genome Project, the field of human genetics has been in great flux, largely due to technological advances in studying DNA sequence variation. Although community-wide adoption of statistical standards was key to the success of genome-wide association studies, similar standards have not yet been globally applied to the processing and interpretation of sequencing data. It has proven particularly challenging to pinpoint unequivocally disease variants in sequencing studies of polygenic traits. Here, we comment on a number of factors that may contribute to irreproducible claims of association in scientific literature and discuss possible steps that we can take towards cultural change.
Published: 2014

31. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author: Nora Franceschini, Yen Pei C. Chang, Susan Kirkland, Aravinda Chakravarti, Alice Stanton, Erik P A Van Iperen, Ilja M. Nolte, Jonathan A. Shaffer, Christopher P. Nelson, Aeilko H. Zwinderman, G. Kees Hovingh, Paul I.W. de Bakker, Christian Gieger, Shen Haiqing, John M. C. Connell, Xiaofeng Zhu, Patricia B. Munroe, Thomas S. Price, Eric Boerwinkle, Deepak L. Bhatt, Santhi K. Ganesh, Anna F. Dominiczak, Caitrin W. McDonough, Harold Snieder, Vinicius Tragante, Albertine J. Oldehinkel, Eoin O'Brien, Barbara E.K. Klein, Alexander P. Reiner, Mary E. Fischer, N. Charlotte Onland-Moret, Kate Witkowska, Christopher Newton-Cheh, Andrew D. Johnson, Laura Steele, Lynda M. Rose, Li Zhang, Erin N. Smith, Mark J. Caulfield, Sharon B. Wyatt, Morris Brown, Martin D. Tobin, Christian Delles, Gail P. Jarvik, Tom R. Gaunt, Hans L. Hillege, Steffi Maiwald, Nilesh J. Samani, Wolfgang Koenig, Konrad J. Karczewski, Julie A. Johnson, Brenda W.J.H. Penninx, Matthijs F.L. Meijs, Judith M. Vonk, Yvonne T. van der Schouw, Daniel I. Chasman, John Barnard, J. Hunter Young, Paul M. Ridker, Sean P. Curtis, Marten H. Hofker, Yan Gong, Jeffrey R. O'Connell, Barbara Thorand, Garret A. FitzGerald, Daichi Shimbo, Sonia Shah, Martin Farrall, Ronald P. Stolk, John G. Gums, Amber L. Beitelshees, Juan P. Casas, Pim van der Harst, Daniel Seung Kim, Peter S. Sever, André G. Uitterlinden, Michael Snyder, Brendan J. Keating, Susan Redline, Muredach P. Reilly, Michael V. Holmes, Maciej Tomaszewski, Daniel J. Rader, Sarah S. Murray, Myriam Fornage, Walter Palmas, Karina W. Davidson, Connie R. Bezzina, Gerald S. Berenson, Toby Johnson, Afshin Parsa, Cornelia M. van Duijn, Kandice Kottke-Marchant, Winfried März, Thomas Illig, W M Monique Verschuren, Aaron Isaacs, Matthew B. Lanktree, Amber A. Burt, Hugh Watkins, Daniel Levy, Hakon Hakonarson, Ramachandran S. Vasan, Johannes M.I.H. Gho, Nathan Pankratz, Sandosh Padmanabhan, Michael R. Barnes, Anuj Goel, Berta Almoguera, Xiuqing Guo, Peter J. van der Most, Ronald Klein, Mieke D. Trip, James S. Pankow, George Davey-Smith, Eric E. Schadt, Indrani Halder, Irene Mateo Leach, Meena Kumari, Claire E. Hastie, John J.P. Kastelein, Caroline O. L. Wong, Clara C. Elbers, Folkert W. Asselbergs, Wei Guo, Marcus E. Kleber, Karen J. Cruickshanks, Pieter A. Doevendans, Jane E. Ranchalis, Yun Li, Olle Melander, Jens Baumert, Ron T. Gansevoort, Rhonda M. Cooper-DeHoff, Mary Pettinger, Cisca Wijmenga, Epidemiology, Public Health, Clinical Genetics, Child and Adolescent Psychiatry / Psychology, Internal Medicine, EMGO+ - Mental Health, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Cardiology, Psychiatry, EMGO - Mental health, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Research Institute for Asthma and COPD (GRIAC), and Vascular Ageing Programme (VAP)
Subjects: Quality Control, Candidate gene, Genotype, Systole, Population, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Essential hypertension, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Polymorphism (computer science), Diastole, Risk Factors, medicine, Genetics, Humans, Genetics(clinical), Arterial Pressure, European Continental Ancestry Group/genetics, Polymorphism, education, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Computational Biology, Single Nucleotide, Computational Biology/methods, medicine.disease, 3. Good health, Europe, Genetics, Population, Blood pressure, Phenotype, Genetic Loci, Genome-Wide Association Study
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. © 2014 The American Society of Human Genetics.
Published: 2014

32. The Genome of the Netherlands: design, and project goals

Author: Elisabeth M. van Leeuwen, Jeroen F. J. Laros, Clara C. Elbers, Alexandros Kanterakis, Jessica van Setten, Cisca Wijmenga, Gonneke Willemsen, Vyacheslav Koval, Qibin Li, Sujie Cao, Jouke-Jan Hottenga, Jayne Y. Hehir-Kwa, Laurent C. Francioli, Kai Ye, Jeanine J. Houwing-Duistermaat, Morris A. Swertz, David van Enckevort, Sara L. Pulit, Karol Estrada, Hailiang Mai, Marian Beekman, Anton J. M. de Craen, Gert-Jan B. van Ommen, Ben A. Oostra, Androniki Menelaou, Hongzhi Cao, Martijn Dijkstra, Mathijs Kattenberg, Abdel Abdellaoui, Yingrui Li, Albert Hofman, Cornelia M. van Duijn, Martijn Vermaat, Eline Slagboom, Lennart C. Karssen, Johan T. den Dunnen, Freerk van Dijk, Fernanodo Rivadeneira, Dorret I. Boomsma, Ruoyan Chen, Patrick Deelen, Paul I.W. de Bakker, Peter de Knijff, Bruce H. R. Wolffenbuttel, Ning Li, Heorhiy Byelas, Victor Guryev, Yuanping Du, Pieter B. Neerincx, André G. Uitterlinden, Jun Wang, H. Eka D. Suchiman, Epidemiology, Dermatology, Molecular Genetics, Internal Medicine, Clinical Genetics, Biological Psychology, EMGO+ - Mental Health, Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Adult Psychiatry
Subjects: Adult, Male, Netherlands Twin Register (NTR), TWIN, Population genetics, Computational biology, Human genetic variation, Biology, whole-genome sequence, Genome, DISEASE, Article, COMMON SNPS, Young Adult, Gene Frequency, Databases, Genetic, Genetic variation, Genetics, WIDE ASSOCIATION, Humans, Genetics (clinical), SUSCEPTIBILITY VARIANTS, Aged, Netherlands, Genetic association, RISK, Aged, 80 and over, HERITABILITY, MUTATIONS, Genome, Human, Haplotype, Genetic Variation, High-Throughput Nucleotide Sequencing, population genetics, Sequence Analysis, DNA, Middle Aged, Biobank, FAMILY, Phylogeography, Female, Imputation (genetics), trio-design
Abstract: Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project. © 2014 Macmillan Publishers Limited All rights reserved.
Published: 2014

33. LDL-c-linked SNPs are associated with LDL-c and myocardial infarction despite lipid-lowering therapy in patients with established vascular disease

Author: Paul I.W. de Bakker, Frank L.J. Visseren, Yolanda van der Graaf, Ale Algra, Folkert W. Asselbergs, Gert J. de Borst, Wilko Spiering, and Anton P. van de Woestijne
Subjects: Male, medicine.medical_specialty, Statin, Genotype, medicine.drug_class, Clinical Biochemistry, Population, Myocardial Infarction, Single-nucleotide polymorphism, Pharmacology, Polymorphism, Single Nucleotide, Biochemistry, Gastroenterology, Coronary artery disease, Internal medicine, medicine, Humans, Prospective Studies, Vascular Diseases, Myocardial infarction, Prospective cohort study, education, Aged, education.field_of_study, Vascular disease, business.industry, Anticholesteremic Agents, PCSK9, Serine Endopeptidases, Cholesterol, LDL, General Medicine, medicine.disease, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, business
Abstract: Background Several single-nucleotide polymorphisms (SNPs) are associated with both plasma low-density lipoprotein cholesterol (LDL-c) level and coronary artery disease in the general population. It is unclear whether these associations also apply to patients with vascular disease and whether the associations are independent of lipid-lowering therapy. Design Single-nucleotide polymorphisms associated with plasma LDL-c and vascular risk in the general population (rs11206510 (PCSK9), rs1122608 (LDLR), rs579459 (ABO) and rs599839 (SORT1)) were genotyped in a prospective cohort study of 5482 patients with vascular disease. We determined the association between LDL-c-associated alleles and plasma LDL-c levels and the risk of new vascular events. Results All tested SNPs were associated with LDL-c plasma levels with a magnitude between +0·06 (95% CI 0·02–0·10) mM and +0·14 (95% CI 0·09–0·18) mM per LDL-c-increasing allele. The associations were independent of the use of lipid-lowering medication, except for rs579459, for which the association was not present in patients using lipid-lowering medication. In patients with 7–8 risk alleles for these SNPs, 59% of the patients treated with lipid-lowering medication did not reach the LDL-c target of
Published: 2013

34. Association of Granulomatosis With Polyangiitis (Wegener's) WithHLA-DPB1*04andSEMA6AGene Variants: Evidence From Genome-Wide Analysis

Author: Gang Xie, Robert Spiera, Tabitha N. Kung, Christopher I. Amos, Gary S. Hoffman, John H. Stone, Emily Y. Lu, Paul I.W. de Bakker, Soumya Raychaudhuri, Keisha Carrington, Peter A. Merkel, Steven R. Ytterberg, Nader Khalidi, Steven S. Zhang, Lindsay A. Farrer, Sara L. Pulit, Carol A. Langford, E. William St. Clair, Stephan Ripke, Delnaz Roshandel, Richard Sherva, Alfred Mahr, Simon Carette, Paul F. Dellaripa, Paul A. Monach, Katherine A. Siminovitch, Ulrich Specks, Jeffrey C. Edberg, and Philip Seo
Subjects: Genetics, HLA-DPB1, Immunology, Haplotype, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, medicine.disease, Rheumatology, medicine, Immunology and Allergy, SNP, Pharmacology (medical), Granulomatosis with polyangiitis, Allele frequency
Abstract: Objective To identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA). Methods We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. Results Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8). Conclusion We identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.
Published: 2013

35. The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk

Author: Vinicius Tragante, Folkert W. Asselbergs, Ale Algra, Pieter A. Doevendans, Yolanda van der Graaf, Gert J. de Borst, Paul I.W. de Bakker, Wilko Spiering, and Hendrik M. Nathoe
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Genotype, Myocardial Infarction, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Type 2 diabetes, Polymorphism, Single Nucleotide, Coronary artery disease, Peripheral Arterial Disease, Young Adult, Recurrence, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Myocardial infarction, Aged, Proportional hazards model, business.industry, Hazard ratio, Middle Aged, medicine.disease, Stroke, Genetic Loci, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Body mass index, Aortic Aneurysm, Abdominal, Genome-Wide Association Study
Abstract: Aims Genome-wide association studies (GWAS) have identified many genetic loci related to coronary artery disease (CAD) and myocardial infarction (MI). However, the extent to which these loci are related to other vascular diseases is not clear. The aim of this study is to investigate the cumulative effects of risk alleles associated with CAD/MI on ischaemic stroke (IS), abdominal aortic aneurysm (AAA), and peripheral artery disease (PAD). Methods and results We calculated a multi-locus genetic risk score (GRS) in 8446 participants of the SMART (Second Manifestations of ARTerial disease) study based on the lead single-nucleotide polymorphisms (SNPs) at 30 CAD/MI loci, and tested this GRS for cross-sectional association with CAD/MI, IS, AAA and PAD, adjusting for age and sex. We also investigated whether this GRS was associated with recurrent vascular events using Cox regression, adjusting for age, sex, body mass index, type 2 diabetes, low-density lipoprotein-cholesterol, smoking, and hypertension. We found that the GRS was significantly associated with CAD ( P = 1.31 × 10−9), IS ( P = 0.030), and PAD ( P = 6.93 × 10−04), but not with AAA ( P = 0.057). The lead SNP at the 9p21 locus (rs4977574) was associated with all four vascular diseases ( P < 4 × 10−3), illustrating the functional pleiotropy of this locus. The GRS was associated with recurrent risk of MI ( P = 0.026), with a hazard ratio of 1.13 (95% CI 1.00–1.28) for individuals in the top quartile of the GRS distribution ( n = 30 recurrent events) compared with those in the bottom quartile ( n = 8 recurrent events). Finally, we found a significant positive relationship between the GRS and the number of vascular events ( P = 3.26 × 10−05). Conclusions These findings suggest that CAD/MI-associated risk alleles play an aetiological role in different types of atherosclerotic disease.
Published: 2013

36. Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk

Author: Lucia Conde, Paige M. Bracci, Xiaoming Jia, Ishak D. Irwan, Henrik Hjalgrim, Karin E. Smedby, Bengt Glimelius, Hans-Olov Adami, Mattias Berglund, Christine F. Skibola, Hatef Darabi, Mads Melbye, Leonid Padyukov, Chiea Chuen Khor, Jianjun Liu, Yi Li, Gunilla Enblad, Nicholas K. Akers, Paul I.W. de Bakker, Keith Humphreys, and Jia Nee Foo
Subjects: Population, Follicular lymphoma, Single-nucleotide polymorphism, Human leukocyte antigen, Major histocompatibility complex, Polymorphism, Single Nucleotide, 03 medical and health sciences, Open Reading Frames, 0302 clinical medicine, Gene Frequency, Risk Factors, Report, medicine, Confidence Intervals, Genetics, SNP, Humans, Genetic Predisposition to Disease, Genetics(clinical), Amino Acids, education, HLA-DRB1, Lymphoma, Follicular, Genetics (clinical), Alleles, Genetic Association Studies, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, biology, Histocompatibility Testing, medicine.disease, 3. Good health, Genetics, Population, Haplotypes, 030220 oncology & carcinogenesis, Case-Control Studies, biology.protein, HLA-DRB1 Chains
Abstract: Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10−15). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9–6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10−14). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.
Published: 2013
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37. Loci influencing blood pressure identified using a cardiovascular gene-centric array

Author: Braxton D. Mitchell, Wei Chen, Wei Guo, Joseph F. Polak, Wolfgang Koenig, Jonathan A. Shaffer, Christian Gieger, Thomas Illig, Abdullah Kutlar, Jessica van Setten, Matthew B. Lanktree, Pieter A. Doevendans, Nicholas J. Schork, Cisca Wijmenga, G. Kees Hovingh, Christopher Newton-Cheh, Daniel Levy, Marten H. Hofker, Eric E. Schadt, Folkert W. Asselbergs, Nicole Soranzo, Sathanur R. Srinivasan, Olle Mellander, Daniel J. Rader, Roy L. Silverstein, David Duggan, Lynda M. Rose, Ron T. Gansevoort, Cliona Molony, André G. Uitterlinden, Li Zhang, Gerald S. Berenson, John Barnard, Vasan S. Ramachandran, Paul M. Ridker, Toby Johnson, Cornelia M. van Duijn, J. Hunter Young, Martin Farrall, Willem H. Ouwehand, Muredach P. Reilly, Tom S. Price, Sean P. Curtis, Brendan J. Keating, John G. Gums, Deepak L. Bhatt, Ilja M. Nolte, Barbara Thorand, Georg Ehret, Hans L. Hillege, Julie A. Johnson, Bernhard R. Winkelmann, Andrea Z. LaCroix, Patricia B. Munroe, Vinicius Tragante, Alan R. Shuldiner, Mieke D. Trip, Karina W. Davidson, Kandice Kottke-Marchant, Hubert Scharnag, Andrew D. Johnson, Ben Burkley, Clement E. Furlong, Winfried März, Yvonne T. van der Schouw, Yen Pei C. Chang, Hakon Hakonarson, Erin N. Smith, Aaron Isaacs, Eric Boerwinkle, Albertine J. Oldehinkel, Haiqing Shen, Richard R. Fabsitz, Alice Stanton, Steffi Maiwald, Matthijs F.L. Meijs, Johannes M.I.H. Gho, Yan Gong, Herman A. Taylor, Mary E. Fischer, Jeffery R. O'Connell, Santhi K. Ganesh, Rhonda M. Cooper-DeHoff, Ervin R. Fox, Albert W. Dreisbach, Brenda W.J.H. Penninx, Susan Kirkland, Caitrin W. McDonough, Nora Franceschini, Daniel I. Chasman, Amber L. Beitelshees, Carl J. Pepine, Tom R. Gaunt, Gurunathan Murugesan, Pim van der Harst, Irene Mateo Leach, Aravinda Chakravarti, Mary Pettinger, Gail P. Jarvik, Marcus E. Kleber, Paul I.W. de Bakker, Myriam Fornage, Mark J. Caulfield, Amber A. Burt, Judith M. Vonk, Sandosh Padmanabhan, Jane E. Ranchalis, Sonia Shah, Berta Almoguera Castillo, Erik P A Van Iperen, Jolanda M. A. Boer, Kiang Liu, Ronald P. Stolk, Garret A. FitzGerald, Yun Li, Rainer Malik, Jens Baumert, Peter J. van der Most, W. M. Monique Verschuren, Bernhard O. Boehm, Clara C. Elbers, Xiaofeng Zhu, Harold Snieder, N. Charlotte Onland-Moret, Honghuang Lin, Taimour Y. Langaee, Ramakrishnan Rajagopalan, John J.P. Kastelein, Nilesh J. Samani, Daichi Shimbo, Susan Redline, Sarah S. Murray, Alexander P. Reiner, Sharon B. Wyatt, Walter Palmas, Yiran Guo, EMGO+ - Mental Health, Ehret, Georg Benedikt, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Cardiology, Psychiatry, EMGO - Mental health, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Epidemiology, Public Health, Clinical Genetics, Immunology, Child and Adolescent Psychiatry / Psychology, and Internal Medicine
Subjects: Male, Candidate gene, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Bioinformatics, Cohort Studies, 0302 clinical medicine, Polymorphism (computer science), European Continental Ancestry Group/genetics, Genetics (clinical), ddc:616, Genetics, 0303 health sciences, Association Studies Articles, PULSE PRESSURE, Chromosome Mapping, General Medicine, Single Nucleotide, Middle Aged, 3. Good health, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Female, Corrigendum, circulatory and respiratory physiology, EXPRESSION, Adult, Blood Pressure/genetics, Genotype, Single-nucleotide polymorphism, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, White People, Cardiovascular Diseases/genetics/physiopathology, 03 medical and health sciences, MDM2, SDG 3 - Good Health and Well-being, Cardiovascular Diseases/genetics, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, HISTAMINE-RECEPTOR H-1, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, Molecular Biology, Gene, METAANALYSIS, 030304 developmental biology, Aged, P53, HYPERTENSION, MICE, Blood pressure, Methylenetetrahydrofolate reductase, Expression quantitative trait loci, biology.protein, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
Published: 2013

38. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author: Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences
Subjects: Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2016

39. The Duffy antigen receptor for chemokines null promoter variant does not influence HIV-1 acquisition or disease progression

Author: Barton F. Haynes, Amy C. Weintrob, Andrew J. McMichael, David Goldstein, Kevin V. Shianna, Norman L. Letvin, Dongliang Ge, Myron S. Cohen, Samuel P. Dickson, Jacques Fellay, Nicole M. Walley, Bruce D. Walker, Nelson L. Michael, Boris Julg, Paul I.W. de Bakker, and Mary Carrington
Subjects: Chemokine, Cancer Research, Cell, Human immunodeficiency virus (HIV), HIV Infections, Receptors, Cell Surface, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Microbiology, White People, Article, Cohort Studies, Virology, Antigen receptor, Immunology and Microbiology(all), parasitic diseases, medicine, Humans, Receptor, Promoter Regions, Genetic, Molecular Biology, Disease progression, virus diseases, Black or African American, medicine.anatomical_structure, Immunology, HIV-1, biology.protein, Disease Progression, Parasitology, Duffy Blood-Group System
Abstract: Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC −46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC −46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, ∼11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.
Published: 2016

40. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies

Author: Martin D. Tobin, Nilesh J. Samani, Yalda Jamshidi, John M. C. Connell, Daryl Waggott, Rhian Gwilliam, Christopher Newton-Cheh, Panos Deloukas, Andrew D. Paterson, Louise V. Wain, Dan E. Arking, Morris J. Brown, Chris Wallace, Nicholas D. Carter, Irina Savelieva, Paul I.W. de Bakker, Anna F. Dominiczak, Nicole Soranzo, Dongling Zheng, Steve Jeffery, Mark Eijgelsheim, Eleftheria Zeggini, Harold Snieder, Arne Pfeufer, Tim D. Spector, Jingyuan Fu, Mark Lathrop, Patricia B. Munroe, Serena Sanna, Chrysoula Dalageorgou, Martin Farrall, Stephen Newhouse, Kenneth R. Rice, Folkert W. Asselbergs, Ilja M. Nolte, Mark J. Caulfield, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Cardiovascular Disorders/Heart Failure, lcsh:Medicine, Genetics and Genomics/Pharmacogenomics, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Genetics and Genomics/Complex Traits, Bioinformatics, QT interval, Sudden cardiac death, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, NOS1AP, Cardiovascular Disorders/Arrhythmias, Electrophysiology, and Pacing, Genetics and Genomics/Population Genetics, medicine, SNP, Humans, lcsh:Science, Genetics and Genomics/Genetics of Disease, 030304 developmental biology, Genetic association, 0303 health sciences, Multidisciplinary, lcsh:R, Calcium-Binding Proteins, Genetic Variation, Genetics and Genomics, Heart, medicine.disease, 3. Good health, Phospholamban, lcsh:Q, Cardiovascular Disorders/Myopathies, Chromosomes, Human, Pair 6, Research Article, Genome-Wide Association Study
Abstract: To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P−6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4×10−83) and the phospholamban (PLN) gene (P = 1.9×10−29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
Published: 2016

41. Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies

Author: Charleston W. K. Chiang, Eric Boerwinkle, James C. Engert, Alkes L. Price, Thomas S. Price, George J. Papanicolaou, Stephanie DerOhannessian, Mark J. Caulfield, Deborah A. Nickerson, Brendan J. Keating, Andrew T. Hattersley, Wolfgang Koenig, David Reich, A. Stephen Whitehead, Thomas A. Drake, Daniel J. Rader, Eric E. Schadt, Cecelia E. Kim, Thomas P. Cappola, Susanna S. Wang, Kent D. Taylor, Saad Ajmal, A. Jake Lusis, Stacey Gabriel, Michael Boehnke, Mark I. McCarthy, Tamim H. Shaikh, Joel N. Hirschhorn, Sonia S. Anand, Struan F.A. Grant, Nilesh J. Samani, Patricia B. Munroe, Jeffrey C. Barrett, Leif Groop, Alistair S. Hall, Hareesh R. Chandrupatla, Myriam Fornage, Xiaowu Gai, Garret A. FitzGerald, Joseph T. Glessner, Tushar Bhangale, Paul I.W. de Bakker, Muredach P. Reilly, Andrew C. Edmondson, Mingyao Li, Swneke D. Bailey, Sarah S. Murray, Sam Tischfield, Nick Patterson, Deborah N. Farlow, Willem H. Ouwehand, Sekar Kathiresan, Edward C. Frackelton, James G. Wilson, Hakon Hakonarson, Alexandre Montpetit, Richard R. Fabsitz, Mark Hansen, Luana Galver, and Yiran Guo
Subjects: Quality Control, Genotype, Concept Formation, Cardiovascular Disorders, lcsh:Medicine, Genome-wide association study, Single-nucleotide polymorphism, Computational biology, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Population Groups, Genetic model, Humans, International HapMap Project, lcsh:Science, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Multidisciplinary, lcsh:R, Genetics and Genomics, Cardiovascular Diseases, Research Design, Expression quantitative trait loci, Epistasis, lcsh:Q, Genome-Wide Association Study, Research Article, Biotechnology, SNP array
Abstract: A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.
Published: 2016

42. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Author: Joseph Vijai, W. Ryan Diver, Degui Zhi, Brenda M. Birmann, Henrik Hjalgrim, Bruce K. Armstrong, Gianluca Severi, Pierluigi Cocco, Joseph F. Fraumeni, Xifeng Wu, Graham G. Giles, Eleanor Kane, Herve Ghesquieres, Eve Roman, Edward Giovannucci, Mads Melbye, Rudolph Kaaks, Lindsay M. Morton, Nicholas K. Akers, Elizabeth A. Holly, Liming Liang, Patrizio Mazza, Kari E. North, John J. Spinelli, Carrie A. Thompson, Bodil Ohlsson, Yuanqing Ye, Anneclaire J. De Roos, Stephen J. Chanock, Theodore R. Holford, Paul Brennan, Jianjun Liu, Roel Vermeulen, Thomas E. Witzig, Angela Brooks-Wilson, Mark P. Purdue, Ahmet Dogan, Gilles Salles, Kenneth Offit, Lucia Conde, Laurie Burdett, George J. Weiner, Anne Kricker, James McKay, Peter Kraft, Sonja I. Berndt, Attilio Gabbas, Rebecca Montalvan, Rebecca D. Jackson, Baoshan Ma, Zhaoming Wang, Patricia Hartge, Danylo J. Villano, Marc Maynadie, Mortimer J. Lacher, Lauren R. Teras, Susan L. Slager, Lenka Foretova, Rachel S. Kelly, Martha S. Linet, Brian K. Link, Jarmo Virtamo, Charles C. Chung, Anne Zeleniuch-Jacquotte, Martyn T. Smith, Tracy Lightfoot, Jacques Riby, Paolo Boffetta, Meredith Yeager, Brian C.-H. Chiu, Grzegorz S. Nowakowski, Yolanda Benavente, Bengt Glimelius, Mark Liebow, Saioa Chamosa, Charles E. Lawrence, Karin E. Smedby, Nikolaus Becker, Thomas M. Habermann, Jacqueline Clavel, Qing Lan, Alexandra Nieters, Maryjean Schenk, Sophia S. Wang, Demetrius Albanes, Lesley F. Tinker, Alex Smith, Anthony Staines, Amy Hutchinson, Wendy Cozen, Hans-Olov Adami, Anne J. Novak, Christine F. Skibola, Ann Maria, Elisabete Weiderpass, Kimberly A. Bertrand, James R. Cerhan, Maria Grazia Ennas, Claire M. Vajdic, Jinyan Huang, Paul I.W. de Bakker, Paige M. Bracci, Tongzhang Zheng, Ruth C. Travis, Paolo Vineis, Jia Nee Foo, Jennifer Turner, Alain Monnereau, Silvia de Sanjosé, Nathaniel Rothman, Yawei Zhang, Jian Gu, Skibola, C.F., Berndt, S.I., Vijai, J., Conde, L., Wang, Z., Yeager, M., De Bakker, P.I.W., Birmann, B.M., Vajdic, C.M., Foo, J.-N., Bracci, P.M., Vermeulen, R.C.H., Slager, S.L., De Sanjose, S., Wang, S.S., Linet, M.S., Salles, G., Lan, Q., Severi, G., Hjalgrim, H., Lightfoot, T., Melbye, M., Gu, J., Ghesquières, H., Link, B.K., Morton, L.M., Holly, E.A., Smith, A., Tinker, L.F., Teras, L.R., Kricker, A., Becker, N., Purdue, M.P., Spinelli, J.J., Zhang, Y., Giles, G.G., Vineis, P., Monnereau, A., Bertrand, K.A., Albanes, D., Zeleniuch-Jacquotte, A., Gabbas, A., Chung, C.C., Burdett, L., Hutchinson, A., Lawrence, C., Montalvan, R., Liang, L., Huang, J., Ma, B., Liu, J., Adami, H.-O., Glimelius, B., Ye, Y., Nowakowski, G.S., Dogan, A., Thompson, C.A., Habermann, T.M., Novak, A.J., Liebow, M., Witzig, T.E., Weiner, G.J., Schenk, M., Hartge, P., De Roos, A.J., Cozen, W., Zhi, D., Akers, N.K., Riby, J., Smith, M.T., Lacher, M., Villano, D.J., Maria, A., Roman, E., Kane, E., Jackson, R.D., North, K.E., Diver, W.R., Turner, J., Armstrong, B.K., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., McKay, J., Brooks-Wilson, A.R., Zheng, T., Holford, T.R., Chamosa, S., Kaaks, R., Kelly, R.S., Ohlsson, B., Travis, R.C., Weiderpass, E., Clavel, J., Giovannucci, E., Kraft, P., Virtamo, J., Mazza, P., Cocco, P., Ennas, M.G., Chiu, B.C.H., Fraumeni, J.F., Jr., Nieters, A., Offit, K., Wu, X., Cerhan, J.R., Smedby, K.E., Chanock, S.J., and Rothman, N.
Subjects: EXPRESSION, Follicular lymphoma, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, VARIANTS, Polymorphism, Single Nucleotide, follicular lymphoma, HLA Antigens, Polymorphism (computer science), Report, CLASS-I, RESOURCE, Biomarkers, Tumor, Genetics, medicine, Chromosomes, Human, Humans, TOOL, Genetic Predisposition to Disease, Genetics(clinical), PEPTIDE, Allele, Lymphoma, Follicular, Alleles, Genetics (clinical), Genetic association, SNPS, RISK, Genome-wide association, Haplotype, medicine.disease, HLA, Haplotypes, Case-Control Studies, UNIVERSITY, SET, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10 -20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10 -11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10 -10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10 -10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10 -8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRß1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10 -67 to 2.67 × 10 -70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10 -16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10 -9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. © 2014 by The American Society of Human Genetics. All rights reserved.
Published: 2016

43. Variation at HLA-DRB1 is associated with resistance to enteric fever

Author: Jeremy Farrar, Tin Aung, Amit Arjyal, Nguyen Phu Huong Lan, Kar Seng Sim, Le Thi Phuong, Trinh T. B. Tram, Phat Voong Vinh, Cameron P. Simmons, Soumya Raychaudhuri, Stephen Baker, Tran Tinh Hien, Nguyen Tran Chinh, Jia Nee Foo, Nga Tran Vu Thieu, Buddha Basnyat, Zheng Li, Nguyen Thi Hue, Abhilasha Karkey, Yukinori Okada, Katherine L. Anders, Do Nu Hon, Sarah J. Dunstan, Martin L. Hibberd, Olita Shilpakar, Christopher M. Parry, Yik Ying Teo, Ha Vinh, Paul I.W. de Bakker, Chiea Chuen Khor, Buhm Han, Mai Ngoc Lanh, Tan Do, Christiane Dolecek, Sabina Dongol, and Samir Koirala
Subjects: Genetic Markers, Genotype, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Typhoid fever, Article, Nepal, Genetics, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Allele, Typhoid Fever, HLA-DRB1, Alleles, Antigen Presentation, Principal Component Analysis, Models, Statistical, Chromosome Mapping, Odds ratio, medicine.disease, Virology, Minor allele frequency, Vietnam, Genetic marker, Immunology, biology.protein, Regression Analysis, Biomarkers, HLA-DRB1 Chains
Abstract: Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C1. We conducted a genome-wide association study of 432 individuals with blood culture–confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10−10), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10−11) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.
Published: 2016

44. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

Author: Bernhard O. Boehm, Marten H. Hofker, Clara C. Elbers, Sam E. Tischfield, Yvonne T. van der Schouw, Richa Saxena, Caitrin W. McDonough, Kandice Kottke-Marchant, Folkert W. Asselbergs, Heribert Schunkert, L. Adrienne Cupples, Nicole L. Glazer, Philippa J. Talmud, John G. Gums, Wolfgang Koenig, Debbie A Lawlor, Matthew B. Lanktree, Myriam Fornage, Andrea Z. LaCroix, A. H. Zwinderman, Alice V. Stanton, Ronald P. Stolk, Kristian M. Bailey, Jeffery R. O'Connell, James S. Pankow, Jolanda M. A. Boer, Brendan J. Keating, Alan R. Shuldiner, Christian Hengstenberg, Yun Li, Olle Melander, Christian Delles, Gail P. Jarvik, John Whitfield, Stephen Newhouse, Rita P.S. Middelberg, Winfried März, Arthur A.M. Wilde, Patricia B. Munroe, Yan Gong, Herman A. Taylor, Denis C. Shields, Hugh Watkins, Ronald Klein, Charles Kooperberg, Hans L. Hillege, Elina Toskala, Christie M. Ballantyne, Mingyao Li, Suzanne Rafelt, Nilesh J. Samani, Bruce H. R. Wolffenbuttel, Kent R. Bailey, Pieter A. Doevendans, Yii-Der Ida Chen, Jens Baumert, Peter Sever, Vinicius Tragante, Florianne Bauer, Sonia S. Anand, W. M. Monique Verschuren, Braxton D. Mitchell, Barbara Thorand, Daniel I. Swerdlow, Jonathan A. Shaffer, Barbara E.K. Klein, Kiang Liu, Michael Y. Tsai, Neil R Poulter, Nicholas J. Schork, Simon P. R. Romaine, Bernhard M. Kaess, Mark J. Caulfield, Wei Chen, Erin N. Smith, Connie R. Bezzina, Stephen S. Rich, Tushar Bhangale, Leslie A. Lange, Mika Kivimäki, John Barnard, Julie A. Johnson, Roy L. Silverstein, Daichi Shimbo, Yiran Guo, Jessica van Setten, Meena Kumari, Berta Almoguera, Claire E. Hastie, Marcus E. Kleber, Robert A. Hegele, Mieke D. Trip, Matthijs F.L. Meijs, Bruce M. Psaty, Tina Shah, Susan Redline, Eric Boerwinkle, Cisca Wijmenga, Jonas S. Dejong, Catharina A. Hartman, Karen J. Cruickshanks, Taimour Y. Langaee, Amber A. Burt, Niek Verweij, David Duggan, Jerome I. Rotter, Ellen Van Der Schoot, Sathanur R. Srinivasan, N. Charlotte Onland-Moret, Paul Burton, Hakon Hakonarson, Laya Mallela, Fotios Drenos, Yolande Appelman, Rhonda M. Cooper-DeHoff, Peter S. Braund, Eric J. Topol, Michael V. Holmes, Grant W. Montgomery, Hubert Scharnagl, Alexander P. Reiner, Susan Kirkland, Daniel J. Rader, John C. Whittaker, Clement E. Furlong, Suthesh Sivapalaratnam, Gerald S. Berenson, Kiran Musunuru, Steve E. Humphries, Toby Johnson, Sarah S. Murray, Ramakrishnan Rajagopalan, Paul I.W. de Bakker, Erik P A Van Iperen, John J.P. Kastelein, Robert Clarke, Jemma C. Hopewell, Thomas Illig, Wendy S. Post, Anna F. Dominiczak, Christopher P. Nelson, Amber L. Beitelshees, Gurunathan Murugesan, Pim van der Harst, G. Kees Hovingh, Muredach P. Reilly, Karina W. Davidson, John M. C. Connell, Anthony J. Balmforth, James G. Wilson, Jose M. Ordovas, Sarah G. Buxbaum, Tom R. Gaunt, Jana V. van Vliet-Ostaptchouk, Li Zhang, Peter J. van der Most, Ian N. M. Day, Willem H. Ouwehand, Salim Yusuf, Haiqing Shen, Sekar Kathiresan, Nathan Pankratz, Sandosh Padmanabhan, Pamela J. Schreiner, Alistair S. Hall, Juan P. Casas, Nicholas G. Martin, Joost L. Van Pelt, Kelly A. Volcik, Aroon D. Hingorani, Cardiology, ICaR - Heartfailure and pulmonary arterial hypertension, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Landsteiner Laboratory, and Clinical Haematology
Subjects: Male, Candidate gene, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Medical and Health Sciences, 0302 clinical medicine, APOLIPOPROTEIN B-100, Missing heritability problem, MISSING HERITABILITY, 2.1 Biological and endogenous factors, Genetics(clinical), Aetiology, FAMILIAL HYPERCHOLESTEROLEMIA, Genetics (clinical), Genetics, Genetics & Heredity, 0303 health sciences, QUANTITATIVE TRAITS, Single Nucleotide, Biological Sciences, Lipids, 3. Good health, SNP genotyping, PLASMA TRIGLYCERIDES, Cholesterol, Phenotype, DENSITY-LIPOPROTEIN CHOLESTEROL, lipids (amino acids, peptides, and proteins), Female, HDL, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, STATISTICAL-MODEL, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, LDL, 03 medical and health sciences, Sex Factors, Humans, CORONARY-HEART-DISEASE, Polymorphism, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, 030304 developmental biology, Genetic association, COMPLEX TRAITS, Human Genome, Cholesterol, HDL, nutritional and metabolic diseases, Cholesterol, LDL, Atherosclerosis, LifeLines Cohort Study, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. © 2012 The American Society of Human Genetics.
Published: 2016

45. Common variants at 30 loci contribute to polygenic dyslipidemia

Author: Michael Boehnke, Luigi Ferrucci, Aarti Surti, Jaakko Tuomilehto, Karen L. Mohlke, Candace Guiducci, Lee M. Kaplan, Rory Collins, Leena Peltonen, Qiong Yang, Cristen J. Willer, Francis S. Collins, Angelo Scuteri, Christopher J. O'Donnell, Edward G. Lakatta, Serkalem Demissie, Johanna Kuusisto, John C. Chambers, Amy J. Swift, Leif Groop, Markku Laakso, Gina M. Peloso, Sekar Kathiresan, Jouko Sundvall, G. Mark Lathrop, Gonçalo R. Abecasis, Benjamin F. Voight, Jose M. Ordovas, Veikko Salomaa, Eric E. Schadt, Robert Clarke, David Altshuler, David Schlessinger, Diana Zelenika, Pilar Galan, Serge Hercberg, Derrick A Bennett, Kari Kubalanza, Laura J. Scott, Kiran Musunuru, Kathryn L. Lunetta, Serena Sanna, Marju Orho-Melander, L. Adrienne Cupples, Toshiko Tanaka, Gabriel Crawford, Pierre Meneton, Josée Dupuis, Anne U. Jackson, Sarah Parish, Paul I.W. de Bakker, Yun Li, Olle Melander, Mario A. Morken, Manuela Uda, Heather M. Stringham, Lori L. Bonnycastle, Noël P. Burtt, Paul Scheet, Richard N. Bergman, and Jaspal S. Kooner
Subjects: Adult, Male, Multifactorial Inheritance, medicine.medical_specialty, Quantitative Trait Loci, Blood lipids, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, Meta-Analysis as Topic, ANGPTL4, Internal medicine, Genetics, medicine, Humans, RNA, Messenger, Allele, Alleles, Triglycerides, Dyslipidemias, 030304 developmental biology, 0303 health sciences, Triglyceride, Cholesterol, Cholesterol, HDL, Reproducibility of Results, Cholesterol, LDL, Syndrome, Middle Aged, medicine.disease, 3. Good health, Phenotype, Endocrinology, Gene Expression Regulation, Liver, chemistry, Female, lipids (amino acids, peptides, and proteins), Dyslipidemia, Genome-Wide Association Study, Lipoprotein
Abstract: Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
Published: 2016

46. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Author: Aleksey Shatunov, An Goris, John Hardy, Thomas F. Meyer, Sandra D'Alfonso, Christian A. Hübner, Karol Estrada, Susana Pinto, Cristina Moglia, Perry T.C. van Doormaal, Simona Arcuti, Thomas Meitinger, Siddharthan Chandran, Kim A. Staats, Cinzia Bertolin, Peter M. Andersen, Ricardo Rojas-García, William Sproviero, Katie Sidle, François Salachas, Robert Swingler, Anna M. Blokhuis, Thomas M. Ringer, Emily P. McCann, Garth A. Nicholson, Lude Franke, Sven Cichon, Julian Grosskreutz, Markus M. Nöthen, Bernhard Landwehrmeyer, Lukas Tittmann, Jennifer A. Fifita, Christian R. Andres, Alice Vajda, Viviana Pensato, Lauren Elman, Gijs H.P. Tazelaar, Christian Lunetta, Patrick Vourc'h, Christopher Shaw, Gilbert Bensimon, Orla Hardiman, Kuang Lin, Pamela J. Shaw, Alessandro Padovani, Massimiliano Filosto, Jan H. Veldink, Boris Rogelj, Giacomo P. Comi, Matthew C. Kiernan, Philippe Corcia, Giancarlo Logroscino, Ammar Al-Chalabi, Blaž Koritnik, Safaa Saker-Delye, Ian P. Blair, Alexis Brice, Jochen H. Weishaupt, Gianni Sorarù, Maura Brunetti, Alan M. Pittman, Vincenzo Silani, Cindy Maurel, Alexandra Durr, Catherine Lomen-Hoerth, Matthew R. Robinson, Russell L. McLaughlin, Martina Wiedau-Pazos, Chiara Zecca, Nilo Riva, Ashley R. Jones, Andre Franke, Tune H. Pers, Roberto Del Bo, Dominic B. Rowe, Susanne Petri, Sara L. Pulit, John Q. Trojanowski, Wim Robberecht, Christine Payan, Otto W. Witte, Katharine Y. Zhang, Jesus S. Mora, Rick A.A. van der Spek, Urmo Võsa, Kevin P. Kenna, Marcella Rietschel, Milena Radivojkov-Blagojevic, Tino Prell, Philip Van Damme, Leja Dolenc Grošelj, Androniki Menelaou, Beatrice Stubendorff, Cristina Cereda, Kristel R. van Eijk, Leo McCluskey, Jean-François Dartigues, Rosa Capozzo, Markus Weber, Cinzia Tiloca, Michael A. van Es, Wouter van Rheenen, Paul I.W. de Bakker, Carsten Drepper, Bradley N. Smith, Ettore Beghi, Jian Yang, Peter M. Visscher, Hamid Hamzeiy, John Landers, A. Nazli Basak, Hylke M. Blauw, Annelot M. Dekker, Richard W. Orrell, Silvana Penco, Fernando Rivadeneira, Marianne de Visser, Ceren Tunca, Cathryn M. Lewis, Vincent Meininger, Andrea Malaspina, Raymond D. Schellevis, Leonard H. van den Berg, Rosanna Tortelli, Shuna Colville, Anneke J. van der Kooi, Ingo Kurth, Roger Pamphlett, Stéphanie Millecamps, Janez Zidar, Michael Sendtner, Simone de Jong, Roel A. Ophoff, Mamede de Carvalho, Karen E. Morrison, Robbert Jan Stuit, Letizia Mazzini, Jonathan D. Glass, Yesim Parman, Albert Hofman, Lea Leonardis, Naomi R. Wray, Meraida Polak, William J. Brands, Susanne Abdulla, Bernard Muller, Cinzia Gellera, Max Koppers, Pietro Fratta, John Powell, Charles Curtis, Peter Lichtner, Frank P. Diekstra, Adriano Chiò, Isabella Fogh, Federico Casale, Nicholas W. Wood, Katarina Vrabec, André G. Uitterlinden, Vivianna M. Van Deerlin, Gerome Breen, Wolfgang Lieb, Oliver Harschnitz, Nicola Ticozzi, P. Nigel Leigh, R. Jeroen Pasterkamp, Simon Topp, Metka Ravnik-Glavač, Christophe Tzourio, Robert H. Brown, Andrea Calvo, Orietta Pansarasa, Jelena Medic, Albert C. Ludolph, Elisabetta Pupillo, Antonia Ratti, Philippe Amouyel, Repositório da Universidade de Lisboa, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Erasmus MC other, Pediatric Surgery, Internal Medicine, Epidemiology, Neurology, and ANS - Neurodegeneration
Subjects: 0301 basic medicine, Population, EFFICIENT, Genome-wide association study, Locus (genetics), Biology, SUSCEPTIBILITY, SEQUENCE, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Munc18 Proteins, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Comparative Study, Amyotrophic lateral sclerosis, education, POPULATION, Genetic association, Netherlands, PITFALLS, education.field_of_study, HEXANUCLEOTIDE REPEAT, COMPLEX, Project MinE, Amyotrophic Lateral Sclerosis, Proteins, PATHWAYS, FRONTOTEMPORAL DEMENTIA, medicine.disease, Genetic architecture, Cytoskeletal Proteins, 030104 developmental biology, Case-Control Studies, Mutation, ALS, 030217 neurology & neurosurgery, Imputation (genetics), Myelin Proteins, Genome-Wide Association Study
Abstract: Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Published: 2016

47. The multiple testing burden in sequencing-based disease studies of global populations

Author: Sara L. Pulit, Sera A.J. de With, and Paul I.W. de Bakker
Subjects: Genetics, Sample size determination, Multiple comparisons problem, Genome-wide association study, Computational biology, Disease, Biology, Allele frequency, Genotyping, Statistical hypothesis testing, Genetic association
Abstract: Genome-wide association studies (GWAS) of common disease have been hugely successful in implicating loci that modify disease risk. The bulk of these associations have proven robust and reproducible, in part due to community adoption of statistical criteria for claiming significant genotype-phenotype associations. Currently, studies of common disease are rapidly shifting towards the use of sequencing technologies. As the cost of sequencing drops, assembling large samples in global populations is becoming increasingly feasible. Sequencing studies interrogate not only common variants, as was true for genotyping-based GWAS, but variation across the full allele frequency spectrum, yielding many more (independent) statistical tests. We sought to empirically determine genome-wide significance for various analysis scenarios. Using whole-genome sequence data, we simulated sequencing-based disease studies of varying sample size and ancestry. We determined that future sequencing efforts in >2,000 samples should practically employ a genome-wide significance threshold of of p −9, though the threshold does vary with ancestry. Studies of European or East Asian ancestry should set genome-wide significance at approximately p −9, but similar studies of African or South Asian samples should be more stringent (p −9). Because sequencing analysis brings with it many challenges (especially for rare variants), appropriate adoption of a revised multiple test correction will be crucial to avoid irreproducible claims of association.
Published: 2016
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48. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Author: Henrik Hjalgrim, Joseph Vijai, Bengt Glimelius, Kimberly A. Bertrand, Immaculata De Vivo, Eve Roman, Martha Glenn, Nathaniel Rothman, Yolanda Benavente, Zhaoming Wang, Ju-Hyun Park, Anneclaire J. De Roos, John J. Spinelli, Demetrius Albanes, Paul Brennan, Emanuele Angelucci, Mariagrazia Zucca, Qing Lan, Kari E. North, Paige M. Bracci, Mark P. Purdue, Marco Rais, Melissa C. Southey, Alain Monnereau, Ahmet Dogan, Graham G. Giles, Robert J. Klein, Peter Kraft, Lesley F. Tinker, Laurie Burdett, Lucia Conde, Carrie A. Thompson, James McKay, Martyn T. Smith, Göran Roos, Yan W. Asmann, Dennis D. Weisenburger, Elizabeth A. Holly, Thomas E. Witzig, Liming Liang, Paul I.W. de Bakker, Alex Smith, Jarmo Virtamo, Charles E. Lawrence, Patricia Hartge, Karen Curtin, Anthony Staines, Nikolaus Becker, Nicola J. Camp, Charles C. Chung, Degui Zhi, Brenda M. Birmann, W. Ryan Diver, Roel Vermeulen, Sonja I. Berndt, Tongzhang Zheng, Silvia de Sanjosé, Eleanor Kane, James R. Cerhan, Christopher R. Flowers, Joseph F. Fraumeni, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Kenneth Offit, Jinyan Huang, Mads Melbye, Edward Giovannucci, Baoshan Ma, Tracy Lightfoot, Brian K. Link, Richard K. Severson, Theodore R. Holford, Yawei Zhang, Anne Tjønneland, Meredith Yeager, Wendy Cozen, Anne J. Novak, Lauren R. Teras, Claire M. Vajdic, Lisa A. Cannon-Albright, Lenka Foretova, Christine F. Skibola, Sophia S. Wang, Hans-Olov Adami, Andrew D. Zelenetz, Jenny Turner, Paolo Vineis, Corinne Haioun, Hervé Tilly, Anne Zeleniuch-Jacquotte, Thomas M. Habermann, Paolo Boffetta, Jacqueline Clavel, Herve Ghesquieres, Stephanie J. Weinstein, Lindsay M. Morton, Susan L. Slager, Simon Crouch, Gilles Salles, Rachel S. Kelly, Karin E. Smedby, Amy Hutchinson, David G. Cox, Elio Riboli, Jacques Riby, Rebecca D. Jackson, Mark Liebow, Thierry Jo Molina, Danylo J. Villano, Marc Maynadie, Yuanqing Ye, Heiner Boeing, Jian Gu, Brian C.-H. Chiu, Simonetta Di Lollo, Mitchell J. Machiela, Alexandra Nieters, Xifeng Wu, Rudolph Kaaks, Machiela, M.J., Lan, Q., Slager, S.L., Vermeulen, R.C.H., Teras, L.R., Camp, N.J., Cerhan, J.R., Spinelli, J.J., Wang, S.S., Nieters, A., Vijai, J., Yeager, M., Wang, Z., Ghesquières, H., McKay, J., Conde, L., de Bakker, P.I.W., Cox, D.G., Burdett, L., Monnereau, A., Flowers, C.R., De Roos, A.J., Brooks-Wilson, A.R., Giles, G.G., Melbye, M., Gu, J., Jackson, R.D., Kane, E., Purdue, M.P., Vajdic, C.M., Albanes, D., Kelly, R.S., Zucca, M., Bertrand, K.A., Zeleniuch-Jacquotte, A., Lawrence, C., Hutchinson, A., Zhi, D., Habermann, T.M., Link, B.K., Novak, A.J., Dogan, A., Asmann, Y.W., Liebow, M., Thompson, C.A., Ansell, S.M., Witzig, T.E., Tilly, H., Haioun, C., Molina, T.J., Hjalgrim, H., Glimelius, B., Adami, H.-O., Roos, G., Bracci, P.M., Riby, J., Smith, M.T., Holly, E.A., Cozen, W., Hartge, P., Morton, L.M., Severson, R.K., Tinker, L.F., North, K.E., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., Lightfoot, T., Crouch, S., Smith, A., Roman, E., Ryan Diver, W., Offit, K., Zelenetz, A., Klein, R.J., Villano, D.J., Zheng, T., Zhang, Y., Holford, T.R., Turner, J., Southey, M.C., Clavel, J., Virtamo, J., Weinstein, S., Riboli, E., Vineis, P., Kaaks, R., Boeing, H., Tjønneland, A., Angelucci, E., Di Lollo, S., Rais, M., De Vivo, I., Giovannucci, E., Kraft, P., Huang, J., Ma, B., Ye, Y., Chiu, B.C.H., Liang, L., Park, J.-H., Chung, C.C., Weisenburger, D.D., Fraumeni, J.F., Jr and Salles, G., Glenn, M., Cannon-Albright, L., Curtin, K., Wu, X., Smedby, K.E., de Sanjose, S., Skibola, C.F., Berndt, S.I., Birmann, B.M., Chanock, S.J., Rothman, N., LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Cancer environnement ( EPICENE ), Bordeaux population health ( BPH ), Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Registre des hémopathies malignes de la Gironde, Institut Bergonié - CRLCC Bordeaux, Department of Agronomy, University of Wisconsin-Madison [Madison], Service hématologie Poitiers, CHU, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Descartes - Paris 5 ( UPD5 ), Oslo and Akershus University College ( OAUC ), Laboratoire de mécanique Biomécanique Polymère Structures ( LaBPS ), Université de Lorraine ( UL ), The Tisch Cancer Institute, Mount Sinai School of Medicine, International Agency for Cancer Research ( IACR ), International Agency for Cancer Research, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), University of Chicago Medicine, Institut National de la Santé et de la Recherche Médicale ( INSERM ), French National Registry of Childhood Hematological malignancies (NRCH), NRCH, Division of Epidemiology, Public Health and Primary Care, Imperial College London, Unit of Cancer Epidemiology, AOU S. Giovanni Battista, CPO Piemonte, CeRMS, University of Torino, Department of Epidemiology and Public Health, Department Cancer Epidemiology, German Cancer Research Center, Institute of Human Nutrition Potsdam-Rehbruecke, Diet, Cancer and Health, Danish Cancer Society, Justus Liebig University Giessen, Sino French Research Center for Biomedical Imaging ( HIT-INSA ), Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Harbin Institute of Technology ( HIT ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Chinese Academy of Sciences [Beijing] ( CAS ), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer environnement (EPICENE ), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, University of Wisconsin-Madison, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Descartes - Paris 5 (UPD5), Akershus University College, Laboratoire de mécanique Biomécanique Polymère Structures (LaBPS), Université de Lorraine (UL), Icahn School of Medicine at Mount Sinai [New York] (MSSM), International Agency for Cancer Research (IACR), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Justus-Liebig-Universität Gießen (JLU), Sino French Research Center for Biomedical Imaging (HIT-INSA), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Harbin Institute of Technology (HIT), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chinese Academy of Sciences [Beijing] (CAS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Harbin Institute of Technology (HIT), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Oslo and Akershus University College (OAUC), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: 0301 basic medicine, Serum, Male, Lymphoma, analysis, Chronic lymphocytic leukemia, Follicular lymphoma, Global Health, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, immunology, surgery, 0302 clinical medicine, Endocrinology, immune system diseases, single nucleotide polymorphism, Germany, hemic and lymphatic diseases, London, 80 and over, Odds Ratio, genetics, Prospective Studies, B-cell lymphoma, Association Studies Article, Genetics (clinical), Aged, 80 and over, education.field_of_study, telomere, Genome, Leukemia, Age Factors, General Medicine, Environmental exposure, Genomics, Middle Aged, b-cell lymphoma, small cell lymphoma, Italy, 030220 oncology & carcinogenesis, Medicine, epidemiology, Female, France, Risk of B-cell lymphoma subtypes, Risk, Adult, Canada, China, Lymphoma, B-Cell, Genotype, Adolescent, leukocytes, etiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Environment, Risk Assessment, methods, Time, 03 medical and health sciences, medicine, Humans, Family, Genetic Predisposition to Disease, education, Molecular Biology, Alleles, Occupational Health, Genetic Association Studies, Aged, B-Cell, International Agencies, Odds ratio, Environmental Exposure, medicine.disease, Telomere, Non-Hodgkin's lymphoma, 030104 developmental biology, Immunology, physiology, Chronic Disease, pathology, Laboratories, metabolism
Abstract: International audience; Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk
Published: 2016

49. Extensive Association of Common Disease Variants with Regulatory Sequence

Author: Folkert W. Asselbergs, Magdalena Harakalova, Edward E. S. Nieuwenhuis, Paul I.W. de Bakker, and Michal Mokry
Subjects: Male, Epigenomics, 0301 basic medicine, Gene Expression, lcsh:Medicine, Genome-wide association study, Coronary Artery Disease, Disease, Regulatory Sequences, Nucleic Acid, Vascular Medicine, Coronary artery disease, Adrenal Glands, Medicine and Health Sciences, Coronary Heart Disease, Medicine, Coding region, lcsh:Science, Genetics, Multidisciplinary, Chromosome Biology, Neurodegenerative Diseases, Genomics, Chromatin, 3. Good health, Immune System Diseases, Neurology, Regulatory sequence, Female, Epigenetics, Anatomy, Databases, Nucleic Acid, Research Article, Adult, DNA transcription, Cardiology, Endocrine System, Gastroenterology and Hepatology, 03 medical and health sciences, Immune system, Alzheimer Disease, Mental Health and Psychiatry, Genome-Wide Association Studies, Journal Article, Humans, Genetic association, business.industry, Inflammatory Bowel Disease, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, Inflammatory Bowel Diseases, Genome Analysis, medicine.disease, 030104 developmental biology, Dementia, lcsh:Q, business, Genome-Wide Association Study
Abstract: Overlap between non-coding DNA regulatory sequences and common variant associations can help to identify specific cell and tissue types that are relevant for particular diseases. In a systematic manner, we analyzed variants from 94 genome-wide association studies (reporting at least 12 loci at p
Published: 2016

50. The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans

Author: Justyna Wasielica-Berger, Giovanni Sarnelli, Antonio Ruiz de León, Michael Vieth, Anders Thorell, Magdalena Gawron-Kiszka, Michaela Müller, Andrzej Dąbrowski, Per Hall, Jonna Bister, V. Annese, Markus M. Nöthen, Burkhard H.A. von Rahden, Magnus Nilsson, Guy E. Boeckxstaens, Anna Mokrowiecka, Cisca Wijmenga, Julio Perez de la Serna, Leszek Paradowski, Marek L. Kowalski, Henning G. Schulz, Uberto Fumagalli, Tomasz Marek, Marek Majewski, Stephan L. Haas, Johannes Schumacher, Agata Mulak, Srdjan Kostic, Riccardo Rosati, Grzegorz Wallner, Till Schwämmle, Lothar Veits, Marek Hartleb, Zeeshan Ateeb, Michael Knapp, Jessica Becker, Anna Latiano, Paul I.W. de Bakker, Ines Gockel, Stefan Niebisch, Elena Urcelay, Krystian Adrych, Mats Lindblad, Frank Lenze, Hauke Lang, Anita Gąsiorowska, Ewa Małecka-Panas, Luigi Laghi, Mira M. Wouters, Timo Hess, Maria Janiak, Anna Dziurkowska-Marek, Peter Elbe, Rosario Cuomo, Jose Luis Santiago, Kamila Czene, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Department of Health and Life Sciences, Becker, Jessica, Haas, Stephan L, Mokrowiecka, Anna, Wasielica Berger, Justyna, Ateeb, Zeeshan, Bister, Jonna, Elbe, Peter, Kowalski, Marek, Gawron Kiszka, Magdalena, Majewski, Marek, Mulak, Agata, Janiak, Maria, Wouters, Mira M, Schwämmle, Till, Hess, Timo, Veits, Lothar, Niebisch, Stefan, Santiago, José L, de León, Antonio Ruiz, de la Serna, Julio Pérez, Urcelay, Elena, Annese, Vito, Latiano, Anna, Fumagalli, Uberto, Rosati, Riccardo, Laghi, Luigi, Cuomo, Rosario, Lenze, Frank, Sarnelli, Giovanni, Müller, Michaela, von Rahden, Burkhard HA, Wijmenga, Cisca, Lang, Hauke, Czene, Kamila, Hall, Per, de Bakker, Paul IW, Vieth, Michael, Nöthen, Markus M, Schulz, Henning G, Adrych, Krystian, Gąsiorowska, Anita, Paradowski, Leszek, Wallner, Grzegorz, Boeckxstaens, Guy E, Gockel, Ine, Hartleb, Marek, Kostic, Srdjan, Dziurkowska Marek, Anna, Lindblad, Mat, Nilsson, Magnu, Knapp, Michael, Thorell, Ander, Marek, Tomasz, Dąbrowski, Andrzej, Małecka Panas, Ewa, Schumacher, Johannes, Schumacher, J, Becker, J, Haas, S, Mokrowiecka, A, Wasielica Berger, J, Ateeb, Z, Bister, J, Elbe, P, Kowalski, M, Gawron Kiszka, M, Majewski, M, Mulak, A, Janiak, M, Wouters, M, Schwämmle, T, Hess, T, Veits, L, Niebisch, S, Santiago, Jl, Ruiz de León, A, Pérez de la Serna, J, Urcelay, E, Annese, V, Latiano, A, Fumagalli, U, Laghi, L, Cuomo, R, Lenze, F, Sarnelli, G, Müller, M, von Rahden, B, Wijmenga, C, Lang, H, Czene, K, Hall, P, de Bakker, P, Vieth, M, Nöthen, M, Schulz, H, Adrych, K, Gąsiorowska, A, Paradowski, L, Wallner, G, Boeckxstaens, G, Gockel, I, Hartleb, M, Kostic, S, Dziurkowska Marek, A, Lindblad, Nilsson, M, Knapp, M, Thorell, A, Marek, T, Dąbrowski, A, and Małecka Panas, E.
Subjects: 0301 basic medicine, Male, European Continental Ancestry Group, Short Report, Achalasia, Human leukocyte antigen, White People, 03 medical and health sciences, 0302 clinical medicine, Swedish population, Genetic, Genetics, esophageal achalasia, Mutation Rate, Genetics, medicine, otorhinolaryngologic diseases, Prevalence, HLA-DQ beta-Chains, Humans, In patient, Esophagus, Risk factor, Genetics (clinical), HLA-DQ beta-Chain, Polymorphism, Genetic, business.industry, European population, medicine.disease, Esophageal Achalasia, Europe, Mutagenesis, Insertional, 030104 developmental biology, medicine.anatomical_structure, Attributable risk, 030211 gastroenterology & hepatology, Female, business, Human, Demography
Abstract: Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 × 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.European Journal of Human Genetics advance online publication, 6 January 2016; doi:10.1038/ejhg.2015.262. ispartof: European Journal of Human Genetics vol:24 issue:8 pages:1228-1231 ispartof: location:England status: published
Published: 2016

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