Author: "Perola, M. (Markus)" - Searchworks@Jio Institute Digital Library Search Results

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109 results on '"Perola, M. (Markus)"'

1. Longitudinal metabolomics of increasing body-mass index and waist-hip ratio reveals two dynamic patterns of obesity pandemic

Author: Mäkinen, V.-P. (Ville-Petteri), Kettunen, J. (Johannes), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Viikari, J. (Jorma), Perola, M. (Markus), Salomaa, V. (Veikko), Järvelin, M.-R. (Marjo-Riitta), Raitakari, O. T. (Olli T.), Ala-Korpela, M. (Mika), Mäkinen, V.-P. (Ville-Petteri), Kettunen, J. (Johannes), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Viikari, J. (Jorma), Perola, M. (Markus), Salomaa, V. (Veikko), Järvelin, M.-R. (Marjo-Riitta), Raitakari, O. T. (Olli T.), and Ala-Korpela, M. (Mika)
Abstract: Background/Objectives: This observational study dissects the complex temporal associations between body-mass index (BMI), waist-hip ratio (WHR) and circulating metabolomics using a combination of longitudinal and cross-sectional population-based datasets and new systems epidemiology tools. Subjects/Methods: Firstly, a data-driven subgrouping algorithm was employed to simplify high-dimensional metabolic profiling data into a single categorical variable: a self-organizing map (SOM) was created from 174 metabolic measures from cross-sectional surveys (FINRISK, n = 9708, ages 25–74) and a birth cohort (NFBC1966, n = 3117, age 31 at baseline, age 46 at follow-up) and an expert committee defined four subgroups of individuals based on visual inspection of the SOM. Secondly, the subgroups were compared regarding BMI and WHR trajectories in an independent longitudinal dataset: participants of the Young Finns Study (YFS, n = 1286, ages 24–39 at baseline, 10 years follow-up, three visits) were categorized into the four subgroups and subgroup-specific age-dependent trajectories of BMI, WHR and metabolic measures were modelled by linear regression. Results: The four subgroups were characterised at age 39 by high BMI, WHR and dyslipidemia (designated TG-rich); low BMI, WHR and favourable lipids (TG-poor); low lipids in general (Low lipid) and high low-density-lipoprotein cholesterol (High LDL-C). Trajectory modelling of the YFS dataset revealed a dynamic BMI divergence pattern: despite overlapping starting points at age 24, the subgroups diverged in BMI, fasting insulin (three-fold difference at age 49 between TG-rich and TG-poor) and insulin-associated measures such as triglyceride-cholesterol ratio. Trajectories also revealed a WHR progression pattern: despite different starting points at the age of 24 in WHR, LDL-C and cholesterol-associated measures, all subgroups exhibited similar rates of change in these measures, i.e. WHR progression was uniform regardless of the
Published: 2023

2. Cross-sectionally calculated metabolic aging does not relate to longitudinal metabolic changes:support for stratified aging models

Author: Ala-Korpela, M. (Mika), Lehtimäki, T. (Tero), Kähönen, M. (Mika), Viikari, J. (Jorma), Perola, M. (Markus), Salomaa, V. (Veikko), Kettunen, J. (Johannes), Raitakari, O. T. (Olli T.), Mäkinen, V.-P. (Ville-Petteri), Ala-Korpela, M. (Mika), Lehtimäki, T. (Tero), Kähönen, M. (Mika), Viikari, J. (Jorma), Perola, M. (Markus), Salomaa, V. (Veikko), Kettunen, J. (Johannes), Raitakari, O. T. (Olli T.), and Mäkinen, V.-P. (Ville-Petteri)
Abstract: Context: Aging varies between individuals, with profound consequences for chronic diseases and longevity. One hypothesis to explain the diversity is a genetically regulated molecular clock that runs differently between individuals. Large human studies with long enough follow-up to test the hypothesis are rare due to practical challenges, but statistical models of aging are built as proxies for the molecular clock by comparing young and old individuals cross-sectionally. These models remain untested against longitudinal data. Objective: We applied novel methodology to test if cross-sectional modeling can distinguish slow vs accelerated aging in a human population. Methods: We trained a machine learning model to predict age from 153 clinical and cardiometabolic traits. The model was tested against longitudinal data from another cohort. The training data came from cross-sectional surveys of the Finnish population (n = 9708; ages 25–74 years). The validation data included 3 time points across 10 years in the Young Finns Study (YFS; n = 1009; ages 24–49 years). Predicted metabolic age in 2007 was compared against observed aging rate from the 2001 visit to the 2011 visit in the YFS dataset and correlation between predicted vs observed metabolic aging was determined. Results: The cross-sectional proxy failed to predict longitudinal observations (R2 = 0.018%, P = 0.67). Conclusion: The finding is unexpected under the clock hypothesis that would produce a positive correlation between predicted and observed aging. Our results are better explained by a stratified model where aging rates per se are similar in adulthood but differences in starting points explain diverging metabolic fates.
Published: 2023

3. Genetic and observational evidence:no independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment

Author: Kuusisto, S. (Sanna), Karjalainen, M. K. (Minna K.), Tillin, T. (Therese), Kangas, A. J. (Antti J.), Holmes, M. V. (Michael V.), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Viikari, J. (Jorma), Perola, M. (Markus), Chaturvedi, N. (Nishi), Salomaa, V. (Veikko), Raitakari, O. T. (Olli T.), Järvelin, M.-R. (Marjo-Riitta), Kettunen, J. (Johannes), Ala-Korpela, M. (Mika), Kuusisto, S. (Sanna), Karjalainen, M. K. (Minna K.), Tillin, T. (Therese), Kangas, A. J. (Antti J.), Holmes, M. V. (Michael V.), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Viikari, J. (Jorma), Perola, M. (Markus), Chaturvedi, N. (Nishi), Salomaa, V. (Veikko), Raitakari, O. T. (Olli T.), Järvelin, M.-R. (Marjo-Riitta), Kettunen, J. (Johannes), and Ala-Korpela, M. (Mika)
Abstract: Background: Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited. Objectives: A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC. Participants/Methods: Six independent cohorts were included with follow-up data for 14,438 participants to investigate the associations of HDL-related measures with incident CHD (1,570 events). The GWAS of HDL-CEC was carried out in 20,372 participants. Results: HDL-CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL-C). In contradiction, almost all HDL-related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL-CEC independent of HDL-C and triglycerides. Conclusions: HDL-CEC is not unequivocally associated with CHD in contrast to HDL-C, apolipoprotein A-I, and most of the HDL subclass particle concentrations.
Published: 2022

4. Association between mitochondrial DNA haplogroups J and K, serum branched-chain amino acids and lowered capability for endurance exercise

Author: Kiiskilä, J. M. (Jukka M.), Hassinen, I. E. (Ilmo E.), Kettunen, J. (Johannes), Kytövuori, L. (Laura), Mikkola, I. (Ilona), Härkönen, P. (Pirjo), Jokelainen, J. J. (Jari J.), Keinänen-Kiukaanniemi, S. (Sirkka), Perola, M. (Markus), Majamaa, K. (Kari), Kiiskilä, J. M. (Jukka M.), Hassinen, I. E. (Ilmo E.), Kettunen, J. (Johannes), Kytövuori, L. (Laura), Mikkola, I. (Ilona), Härkönen, P. (Pirjo), Jokelainen, J. J. (Jari J.), Keinänen-Kiukaanniemi, S. (Sirkka), Perola, M. (Markus), and Majamaa, K. (Kari)
Abstract: Background: Endurance exercise training promotes the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles. We have previously shown that mitochondrial DNA (mtDNA) haplogroups J and K are markers of low responders in endurance training. In this paper, we hypothesize that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups. We evaluated whether exercise-induced changes in amino acid concentrations differ between subjects harbouring mtDNA haplogroups J or K and those with non-JK haplogroups. Methods: Finnish male conscripts (N = 633) undertook the 12-min Cooper running test at the beginning and end of their military service. The intervention during the service mainly included endurance aerobic exercise and sports-related muscle training. Concentrations of seven amino acids were analysed in the serum using a high-throughput ¹H NMR metabolomics platform. Total DNA was extracted from whole blood, and restriction fragment analysis was used to determine mtDNA haplogroups J and K. Results: The concentrations of the seven amino acids were higher following the intervention, with the exception of phenylalanine; interestingly, the increase in the concentrations of three BCAAs was larger in subjects with haplogroup J or K than in subjects with non-JK haplogroups (p = 0.029). MtDNA haplogroups J and K share two common nonsynonymous variants. Structural analysis based on crystallographic data on bovine complexes I and III revealed that the Leu18 variant in cytochrome b encoded by m.14798T > C may interfere with ubiquinone binding at the Qi site in complex III. Conclusions: The increase in the concentrations of serum BCAAs following exercise intervention differs between subjects harbouring mtDNA haplogroup J or K and those harbouring non-JK haplogroups. Lower response in endurance training and difference in exercise-induced increase in the concentrations of serum BCAAs suggest decreased respiratory cha
Published: 2022

5. Comprehensive biomarker profiling of hypertension in 36 985 Finnish individuals

Author: Palmu, J. (Joonatan), Tikkanen, E. (Emmi), Havulinna, A. S. (Aki S.), Vartiainen, E. (Erkki), Lundqvist, A. (Annamari), Ruuskanen, M. O. (Matti O.), Perola, M. (Markus), Ala-Korpela, M. (Mika), Jousilahti, P. (Pekka), Würtz, P. (Peter), Salomaa, V. (Veikko), Lahti, L. (Leo), Niiranen, T. (Teemu), Palmu, J. (Joonatan), Tikkanen, E. (Emmi), Havulinna, A. S. (Aki S.), Vartiainen, E. (Erkki), Lundqvist, A. (Annamari), Ruuskanen, M. O. (Matti O.), Perola, M. (Markus), Ala-Korpela, M. (Mika), Jousilahti, P. (Pekka), Würtz, P. (Peter), Salomaa, V. (Veikko), Lahti, L. (Leo), and Niiranen, T. (Teemu)
Abstract: Objective: Previous studies on the association between metabolic biomarkers and hypertension have been limited by small sample sizes, low number of studied biomarkers, and cross-sectional study design. In the largest study to date, we assess the cross-sectional and longitudinal associations between high-abundance serum biomarkers and blood pressure (BP). Methods: We studied cross-sectional (N = 36 985; age 50.5 ± 14.2; 53.1% women) and longitudinal (N = 4197; age 49.4 ± 11.8, 55.3% women) population samples of Finnish individuals. We included 53 serum biomarkers and other detailed lipoprotein subclass measures in our analyses. We studied the associations between serum biomarkers and BP using both conventional statistical methods and a machine learning algorithm (gradient boosting) while adjusting for clinical risk factors. Results: Fifty-one of 53 serum biomarkers were cross-sectionally related to BP (adjusted P < 0.05 for all). Conventional linear regression modeling demonstrated that LDL cholesterol, remnant cholesterol, apolipoprotein B, and acetate were positively, and HDL particle size was negatively, associated with SBP change over time (adjusted P < 0.05 for all). Adding serum biomarkers (cross-sectional root-mean-square error: 16.27 mmHg; longitudinal: 17.61 mmHg) in the model with clinical measures (cross-sectional: 16.70 mmHg; longitudinal 18.52 mmHg) improved the machine learning model fit. Glucose, albumin, triglycerides in LDL, glycerol, VLDL particle size, and acetoacetate had the highest importance scores in models related to current or future BP. Conclusions: Our results suggest that serum lipids, and particularly LDL-derived and VLDL-derived cholesterol measures, and glucose metabolism abnormalities are associated with hypertension onset. Use of serum metabolite determination could improve identification of individuals at high risk of developing hypertension.
Published: 2022

6. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author: Natarajan, P. (Pradeep), Pampana, A. (Akhil), Graham, S. E. (Sarah E.), Ruotsalainen, S. E. (Sanni E.), Perry, J. A. (James A.), de Vries, P. S. (Paul S.), Broome, J. G. (Jai G.), Pirruccello, J. P. (James P.), Honigbere, M. C. (Michael C.), Aragam, K. (Krishna), Wolford, B. (Brooke), Brody, J. A. (Jennifer A.), Antonacci-Fulton, L. (Lucinda), Arden, M. (Moscati), Aslibekyan, S. (Stella), Assimes, T. L. (Themistocles L.), Ballantyne, C. M. (Christie M.), Bielak, L. F. (Lawrence F.), Bisl, J. C. (Joshua C.), Cade, B. E. (Brian E.), Do, R. (Ron), Doddapaneni, H. (Harsha), Emery, L. S. (Leslie S.), Hung, Y.-J. (Yi-Jen), Irvin, M. R. (Marguerite R.), Khan, A. T. (Alyna T.), Lange, L. (Leslie), Lee, J. (Jiwon), Lemaitre, R. N. (Rozenn N.), Martin, L. W. (Lisa W.), Metcalf, G. (Ginger), Montasser, M. E. (May E.), Moon, J.-Y. (Jee-Young), Muzny, D. (Donna), Connell, J. R. (Jeffrey R. O.), Palmer, N. D. (Nicholette D.), Peralta, J. M. (Juan M.), Peyser, P. A. (Patricia A.), Stilp, A. M. (Adrienne M.), Tsai, M. (Michael), Wang, F. F. (Fei Fei), Weeks, D. E. (Daniel E.), Yanek, L. R. (Lisa R.), Wilson, J. G. (James G.), Abecasis, G. (Goncalo), Arnett, D. K. (Donna K.), Becker, L. C. (Lewis C.), Blangercy, J. (John), Boerwinkle, E. (Eric), Bowden, D. W. (Donald W.), Chang, Y.-C. (Yi-Cheng), Chen, Y. I. (Yii-Der, I), Choi, W. J. (Won Jung), Correa, A. (Adolfo), Curran, J. E. (Joanne E.), Daly, M. J. (Mark J.), DutcherE, S. K. (Susan K.), Ellinor, P. T. (Patrick T.), Fornage, M. (Myriam), Freedman, B. I. (Barry, I), Gabriel, S. (Stacey), Germer, S. (Soren), Gibbs, R. A. (Richard A.), He, J. (Jiang), Hveem, K. (Kristian), Jarvik, G. P. (Gail P.), Kaplan, R. C. (Robert C.), Kardia, S. L. (Sharon L. R.), Kennyn, E. (Eimear), Kim, R. W. (Ryan W.), Kooperberg, C. (Charles), Laurie, C. C. (Cathy C.), Lee, S. (Seonwook), Lloyd-Jones, D. M. (Don M.), Loos, R. J. (Ruth J. F.), Lubitz, S. A. (Steven A.), Mathias, R. A. (Rasika A.), Martinez, K. A. (Karine A. Viaud), McGarvey, S. T. (Stephen T.), Mitche, B. D. (Braxton D.), Nickerson, D. A. (Deborah A.), North, K. E. (Kari E.), Palotie, A. (Aarno), Park, C. J. (Cheol Joo), Psat, B. M. (Bruce M. Y.), Rao, D. C. (D. C.), Redline, S. (Susan), Reiner, A. P. (Alexander P.), Seo, D. (Daekwan), Seo, J.-S. (Jeong-Sun), Smith, A. V. (Albert, V), Tracy, R. P. (Russell P.), Kathiresan, S. (Sekar), Cupples, L. A. (L. Adrienne), Rotten, J. I. (Jerome, I), Morrison, A. C. (Alanna C.), Rich, S. S. (Stephen S.), Ripatti, S. (Samuli), Wilier, C. (Cristen), Peloso, G. M. (Gina M.), Vasan, R. S. (Ramachandran S.), Abe, N. (Namiko), Albert, C. (Christine), Almasy, L. (Laura), Alonso, A. (Alvaro), Ament, S. (Seth), Anderson, P. (Peter), Applebaum-Bowden, D. (Deborah), Arking, D. (Dan), Ashley-Koch, A. (Allison), Auer, P. (Paul), Avramopoulos, D. (Dimitrios), Barnard, J. (John), Barnes, K. (Kathleen), Barr, R. G. (R. Graham), Barron-Casella, E. (Emily), Beaty, T. (Terri), Becker, D. (Diane), Beer, R. (Rebecca), Begum, F. (Ferdouse), Beitelshees, A. (Amber), Benjamin, E. (Emelia), Bezerra, M. (Marcos), Bielak, L. (Larry), Blackwel, T. (Thomas), Bowler, R. (Russell), Broecke, U. (Ulrich), Bunting, K. (Karen), Burchard, E. (Esteban), Buth, E. (Erin), Cardwel, J. (Jonathan), Carty, C. (Cara), Casaburi, R. (Richard), Casella, J. (James), Chaffin, M. (Mark), Chang, C. (Christy), Chasman, D. (Daniel), Chavan, S. (Sameer), Chen, B.-J. (Bo-Juen), Chen, W.-M. (Wei-Min), Chol, M. (Michael), Choi, S. H. (Seung Hoan), Chuang, L.-M. (Lee-Ming), Chung, M. (Mina), Conomos, M. P. (Matthew P.), Cornell, E. (Elaine), Crapo, J. (James), Curtis, J. (Jeffrey), Custer, B. (Brian), Damcott, C. (Coleen), Darbar, D. (Dawood), Das, S. (Sayantan), David, S. (Sean), Davis, C. (Colleen), Daya, M. (Michelle), de Andrade, M. (Mariza), DeBaunuo, M. (Michael), Duan, Q. (Qing), Devine, R. D. (Ranjan Deka Dawn DeMeo Scott), Duggirala, Q. R. (Qing Ravi), Durda, J. P. (Jon Peter), Dutcher, S. (Susan), Eaton, C. (Charles), Ekunwe, L. (Lynette), Farber, C. (Charles), Farnaml, L. (Leanna), Fingerlin, T. (Tasha), Flickinger, M. (Matthew), Franceschini, N. (Nora), Fu, M. (Mao), Fullerton, S. M. (Stephanie M.), Fulton, L. (Lucinda), Gan, W. (Weiniu), Gao, Y. (Yan), Gass, M. (Margery), Ge, B. (Bruce), Geng, X. P. (Xiaoqi Priscilla), Gignoux, C. (Chris), Gladwin, M. (Mark), Glahn, D. (David), Gogarten, S. (Stephanie), Gong, D.-W. (Da-Wei), Goring, H. (Harald), Gu, C. C. (C. Charles), Guan, Y. (Yue), Guo, X. (Xiuqing), Haessler, J. (Jeff), Hall, M. (Michael), Harris, D. (Daniel), Hawle, N. Y. (Nicola Y.), Heavner, B. (Ben), Heckbert, S. (Susan), Hernandez, R. (Ryan), Herrington, D. (David), Hersh, C. (Craig), Hidalgo, B. (Bertha), Hixson, J. (James), Hokanson, J. (John), Hong, E. (Elliott), Hoth, K. (Karin), Hsiung, C. A. (Chao Agnes), Huston, H. (Haley), Hwu, C. M. (Chii Min), Jackson, R. (Rebecca), Jain, D. (Deepti), Jaquish, C. (Cashell), Jhun, M. A. (Min A.), Johnsen, J. (Jill), Johnson, A. (Andrew), Johnson, C. (Craig), Johnston, R. (Rich), Jones, K. (Kimberly), Kang, H. M. (Hyun Min), Kaufman, L. (Laura), Kell, S. Y. (Shannon Y.), Kessler, M. (Michael), Kinney, G. (Greg), Konkle, B. (Barbara), Kramer, H. (Holly), Krauter, S. (Stephanie), Lange, C. (Christoph), Lange, E. (Ethan), Laurie, C. (Cecelia), LeBoff, M. (Meryl), Lee, S. S. (Seunggeun Shawn), Lee, W.-J. (Wen-Jane), LeFaive, J. (Jonathon), Levine, D. (David), Levy, D. (Dan), Lewis, J. (Joshua), Li, Y. (Yun), Lin, H. (Honghuang), Lin, K. H. (Keng Han), Lin, X. (Xihong), Liu, S. (Simin), Liu, Y. (Yongmei), Lunetta, K. (Kathryn), Luo, J. (James), Mahaney, M. (Michael), Make, B. (Barry), Manichaikul, A. (Ani), Mansonl, J. (JoAnn), Margolin, L. (Lauren), Mathai, S. (Susan), McArdle, P. (Patrick), Mcdonald, M.-L. (Merry-Lynn), McFarland, S. (Sean), McHugh, C. (Caitlin), Mei, H. (Hao), Meyers, D. A. (Deborah A.), Mikulla, J. (Julie), Min, N. (Nancy), Minear, M. (Mollie), Minster, R. L. (Ryan L.), Musani, S. (Solomon), Mwasongwe, S. (Stanford), Mychaleckyj, J. C. (Josyf C.), Nadkarni, G. (Girish), Naik, R. (Rakhi), Naseri, T. (Take), Nekhai, S. (Sergei), Nelson, S. C. (Sarah C.), Nickerson, D. (Deborah), Connell, J. O. (Jeff O.), Connor, T. O. (Tim O.), Ochs-Balcom, H. (Heather), Pankow, J. (James), Papanicolaou, G. (George), Parkerl, M. (Margaret), Parsa, A. (Afshin), Penchey, S. (Sara), Perez, M. (Marco), Peters, U. (Ulrike), Phillips, L. S. (Lawrence S.), Phillips, S. (Sam), Pollin, T. (Toni), Post, W. (Wendy), Becker, J. P. (Julia Powers), Boorgula, M. P. (Meher Preethi), Preuss, M. (Michael), Prokopenko, D. (Dmitry), Qasba, P. (Pankaj), Qiao, D. (Dandi), Rafaels, N. (Nicholas), Raffield, L. (Laura), Rasmussen-Torvik, L. (Laura), Ratan, A. (Aakrosh), Reed, R. (Robert), Reganl, E. (Elizabeth), Reupena, M. S. (Muagututi Sefuiva), Rice, K. (Ken), Roden, D. (Dan), Roselli, C. (Carolina), Ruczinski, I. (Ingo), Russel, P. (Pamela), Ruuska, S. (Sarah), Ryan, K. (Kathleen), Sabino, E. C. (Ester Cerdeira), Sakornsakolpatl, P. (Phuwanat), Salzberg, S. (Steven), Sandow, K. (Kevin), Sankaran, V. G. (Vijay G.), Scheller, C. (Christopher), Schmidt, E. (Ellen), Schwander, K. (Karen), Schwartz, D. (David), Sciurba, F. (Frank), Seidman, C. (Christine), Seidman, J. (Jonathan), Sheehan, V. (Vivien), Shetty, A. (Amol), Shetty, A. (Aniket), Sheu, W. H. (Wayne Hui-Heng), Shoemaker, M. B. (M. Benjamin), Silver, B. (Brian), Silvermanl, E. (Edwin), Smith, J. (Jennifer), Smith, J. (Josh), Smith, N. (Nicholas), Smith, T. (Tanja), Smoller, S. (Sylvia), Snively, B. (Beverly), Soferlm, T. (Tamar), Streeten, E. (Elizabeth), Su, J. L. (Jessica Lasky), Sung, Y. J. (Yun Ju), Sylvia, J. (Jody), Sztalryd, C. (Carole), Taliun, D. (Daniel), Tang, H. (Hua), Taub, M. (Margaret), Taylor, K. D. (Kent D.), Taylor, S. (Simeon), Telen, M. (Marilyn), Thornton, T. A. (Timothy A.), Tinker, L. (Lesley), Tirschwel, D. (David), Tiwari, H. (Hemant), Vaidya, D. (Dhananjay), VandeHaar, P. (Peter), Vrieze, S. (Scott), Walker, T. (Tarik), Wallace, R. (Robert), Waits, A. (Avram), Wan, E. (Emily), Wang, H. (Heming), Watson, K. (Karol), Weir, B. (Bruce), Weiss, S. (Scott), Weng, L.-C. (Lu-Chen), Williams, K. (Kayleen), Williams, L. K. (L. Keoki), Wilson, C. (Carla), Wong, Q. (Quenna), Xu, H. (Huichun), Yang, I. (Ivana), Yang, R. (Rongze), Zaghlou, N. (Norann), Zekavat, M. (Maryam), Zhang, Y. (Yingze), Zhao, S. X. (Snow Xueyan), Zhao, W. (Wei), Zni, D. (Degui), Zhou, X. (Xiang), Zhu, X. (Xiaofeng), Zody, M. (Michael), Zoellner, S. (Sebastian), Daly, M. (Mark), Jacob, H. (Howard), Matakidou, A. (Athena), Runz, H. (Heiko), John, S. (Sally), Plenge, R. (Robert), McCarthy, M. (Mark), Hunkapiller, J. (Julie), Ehm, M. (Meg), Waterworth, D. (Dawn), Fox, C. (Caroline), Malarstig, A. (Anders), Klinger, K. (Kathy), Call, K. (Kathy), Mkel, T. (Tomi), Kaprio, J. (Jaakko), Virolainen, P. (Petri), Pulkki, K. (Kari), Kilpi, T. (Terhi), Perola, M. (Markus), Partanen, J. (Jukka), Pitkranta, A. (Anne), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Savinainen, K. (Kimmo), Kosma, V.-M. (Veli-Matti), Kujala, U. (Urho), Tuovila, O. (Outi), Hendolin, M. (Minna), Pakkanen, R. (Raimo), Waring, J. (Jeff), Riley-Gillis, B. (Bridget), Liu, J. (Jimmy), Biswas, S. (Shameek), Diogo, D. (Dorothee), Marshall, C. (Catherine), Hu, X. (Xinli), Gossel, M. (Matthias), Schleutker, J. (Johanna), Arvas, M. (Mikko), Hinttala, R. (Reetta), Kettunen, J. (Johannes), Laaksonen, R. (Reijo), Mannermaa, A. (Arto), Paloneva, J. (Juha), Soininen, H. (Hilkka), Julkunen, V. (Valtteri), Remes, A. (Anne), Klviinen, R. (Reetta), Hiltunen, M. (Mikko), Peltola, J. (Jukka), Tienari, P. (Pentti), Rinne, J. (Juha), Ziemann, A. (Adam), Waring, J. (Jeffrey), Esmaeeli, S. (Sahar), Smaoui, N. (Nizar), Lehtonen, A. (Anne), Eaton, S. (Susan), Landenper, S. (Sanni), Michon, J. (John), Kerchner, G. (Geoff), Bowers, N. (Natalie), Teng, E. (Edmond), Eicher, J. (John), Mehta, V. (Vinay), Gormle, P. Y. (Padhraig Y.), Linden, K. (Kari), Whelan, C. (Christopher), Xu, F. (Fanli), Pulford, D. (David), Frkkil, M. (Martti), Pikkarainen, S. (Sampsa), Jussila, A. (Airi), Blomster, T. (Timo), Kiviniemi, M. (Mikko), Voutilainen, M. (Markku), Georgantas, B. (Bob), Heap, G. (Graham), Rahimov, F. (Fedik), Usiskin, K. (Keith), Maranville, J. (Joseph), Lu, T. (Tim), Oh, D. (Danny), Kalpala, K. (Kirsi), Miller, M. (Melissa), McCarthy, L. (Linda), Eklund, K. (Kari), Palomki, A. (Antti), Isomki, P. (Pia), Piri, L. (Laura), Kaipiainen-Seppnen, O. (Oili), Lertratanaku, A. (Apinya), Bing, D. C. (David Close Marla Hochfeld Nan), Gordillo, J. E. (Jorge Esparza), Mars, N. (Nina), Laitinen, T. (Tarja), Pelkonen, M. (Margit), Kauppi, P. (Paula), Kankaanranta, H. (Hannu), Harju, T. (Terttu), Greenberg, S. (Steven), Chen, H. (Hubert), Betts, J. (Jo), Ghosh, S. (Soumitra), Salomaa, V. (Veikko), Niiranen, T. (Teemu), Juonala, M. (Markus), Metsrinne, K. (Kaj), Khnen, M. (Mika), Junttila, J. (Juhani), Laakso, M. (Markku), Pihlajamki, J. (Jussi), Sinisalo, J. (Juha), Taskinen, M.-R. (Marja-Riitta), Tuomi, T. (Tiinamaija), Laukkanen, J. (Jari), Challis, B. (Ben), Peterson, A. (Andrew), Chu, A. (Audrey), Parkkinen, J. (Jaakko), Muslin, A. (Anthony), Joensuu, H. (Heikki), Meretoja, T. (Tuomo), Aaltonen, L. (Lauri), Auranen, A. (Annika), Karihtala, P. (Peeter), Kauppila, S. (Saila), Auvinen, P. (Pivi), Elenius, K. (Klaus), Popovic, R. (Relja), Schutzman, J. (Jennifer), Loboda, A. (Andrey), Chhibber, A. (Aparna), Lehtonen, H. (Heli), McDonough, S. (Stefan), Crohns, M. (Marika), Kulkarni, D. (Diptee), Kaarniranta, K. (Kai), Turunen, J. (Joni), Ollila, T. (Terhi), Seitsonen, S. (Sanna), Uusitalo, H. (Hannu), Aaltonen, V. (Vesa), Uusitalo-Jrvinen, H. (Hannele), Luodonp, M. (Marja), Hautala, N. (Nina), Strauss, E. (Erich), Chen, H. (Hao), Podgornaia, A. (Anna), Hoffman, J. (Joshua), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Hannula-Jouppi, K. (Katariina), Salmi, T. (Teea), Peltonen, S. (Sirkku), Koulu, L. (Leena), Harvima, I. (Ilkka), Wu, Y. (Ying), Choy, D. (David), Jalanko, A. (Anu), Kajanne, R. (Risto), Lyhs, U. (Ulrike), Kaunisto, M. (Mari), Davis, J. W. (Justin Wade), Quarless, D. (Danjuma), Petrovski, S. (Slav), Chen, C.-Y. (Chia-Yen), Bronson, P. (Paola), Yang, R. (Robert), Chang, D. (Diana), Bhangale, T. (Tushar), Holzinger, E. (Emily), Wang, X. (Xulong), Chen, X. (Xing), Auro, K. (Kirsi), Wang, C. (Clarence), Xu, E. (Ethan), Auge, F. (Franck), Chatelain, C. (Clement), Kurki, M. (Mitja), Karjalainen, J. (Juha), Havulinna, A. (Aki), Palin, K. (Kimmo), Palta, P. (Priit), Parolo, P. D. (Pietro Della Briotta), Zhou, W. (Wei), Lemmel, S. (Susanna), Rivas, M. (Manuel), Harju, J. (Jarmo), Lehisto, A. (Arto), Ganna, A. (Andrea), Llorens, V. (Vincent), Karlsson, A. (Antti), Kristiansson, K. (Kati), Hyvrinen, K. (Kati), Ritari, J. (Jarmo), Wahlfors, T. (Tiina), Koskinen, M. (Miika), Pylkäs, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Mantere, T. (Tuomo), Kangasniemi, E. (Eeva), Heikkinen, S. (Sami), Laakkonen, E. (Eija), Kononen, J. (Juha), Loukola, A. (Anu), Laiho, P. (Pivi), Sistonen, T. (Tuuli), Kaiharju, E. (Essi), Laukkanen, M. (Markku), Jrvensivu, E. (Elina), Lhteenmki, S. (Sini), Mnnikk, L. (Lotta), Wong, R. (Regis), Mattsson, H. (Hannele), Hiekkalinna, T. (Tero), Jimnez, M. G. (Manuel Gonzlez), Donner, K. (Kati), Prn, K. (KaIle), Nunez-Fontarnau, J. (Javier), Kilpelinen, E. (Elina), Sipi, T. P. (Timo P.), Brein, G. (Georg), Dada, A. (Alexander), Awaisa, G. (Ghazal), Shcherban, A. (Anastasia), Sipil, T. (Tuomas), Laivuori, H. (Hannele), Kiiskinen, T. (Tuomo), Siirtola, H. (Harri), Tabuenca, J. G. (Javier Gracia), Kallio, L. (Lila), Soini, S. (Sirpa), Pitknen, K. (Kimmo), and Kuopio, T. (Teijo)
Subjects: Cardiovascular genetics, Genome-wide association studies
Abstract: Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
Published: 2021

7. Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition:a drug-target Mendelian randomization analysis

Author: Wang, Q. (Qin), Oliver-Williams, C. (Clare), Raitakari, O. T. (Olli T.), Viikari, J. (Jorma), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Järvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Perola, M. (Markus), Danesh, J. (John), Kettunen, J. (Johannes), Butterworth, A. S. (Adam S.), Holmes, M. V. (Michael V.), and Ala-Korpela, M. (Mika)
Subjects: Lipoprotein subclasses, ANGPTL4, ANGPTL3, Drug targets, Glycoprotein acetyls, Mendelian randomization, Amino acids, lipids (amino acids, peptides, and proteins), Lipoprotein lipids, LPL
Abstract: Aims: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement. Methods and results: Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function. Conclusions: Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.
Published: 2021

8. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author: Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
Published: 2021

9. Association of circulating metabolites in plasma or serum and risk of stroke:meta-analysis from seven prospective cohorts

Author: Vojinovic, D. (Dina), Kalaoja, M. (Marita), Trompet, S. (Stella), Fischer, K. (Krista), Shipley, M. J. (Martin J.), Li, S. (Shuo), Havulinna, A. S. (Aki S.), Perola, M. (Markus), Salomaa, V. (Veikko), Yang, Q. (Qiong), Sattar, N. (Naveed), Jousilahti, P. (Pekka), Amin, N. (Najaf), Satizabal, C. L. (Claudia L.), Taba, N. (Nele), Sabayan, B. (Behnam), Vasan, R. S. (Ramachandran S.), Ikram, M. A. (M. Arfan), Stott, D. J. (David J.), Ala-Korpela, M. (Mika), Jukema, J. W. (J. Wouter), Seshadri, S. (Sudha), Kettunen, J. (Johannes), Kivimaki, M. (Mika), Esko, T. (Tonu), and van Duijn, C. M. (Cornelia M.)
Abstract: Objective: To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings. Methods: We investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately. Results: The analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 × 10−5), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 × 10−4), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 × 10−3), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 × 10−4) and total and free cholesterol in large HDL particles. Conclusions: We found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.
Published: 2021

10. Metabolic biomarker discovery for risk of peripheral artery disease compared with coronary artery disease:lipoprotein and metabolite profiling of 31 657 individuals from 5 prospective cohorts

Author: Tikkanen, E. (Emmi), Jägerroos, V. (Vilma), Holmes, M. V. (Michael V.), Sattar, N. (Naveed), Ala‐Korpela, M. (Mika), Jousilahti, P. (Pekka), Lundqvist, A. (Annamari), Perola, M. (Markus), Salomaa, V. (Veikko), and Würtz, P. (Peter)
Subjects: biomarker, peripheral artery disease, magnetic resonance spectroscopy, metabolomics, coronary artery disease
Abstract: Background: Peripheral artery disease (PAD) and coronary artery disease (CAD) represent atherosclerosis in different vascular beds. We used detailed metabolic biomarker profiling to identify common and discordant biomarkers and clarify pathophysiological differences for these vascular diseases. Methods and results: We used 5 prospective cohorts from Finnish population (FINRISK 1997, 2002, 2007, and 2012, and Health 2000; n=31 657; median follow‐up time of 14 years) to estimate associations between >200 metabolic biomarkers and incident PAD and CAD. Metabolic biomarkers were measured with nuclear magnetic resonance, and disease events were obtained from nationwide hospital records. During the follow‐up, 498 incident PAD and 2073 incident CAD events occurred. In age‐ and sex‐adjusted Cox models, apolipoproteins and cholesterol measures were robustly associated with incident CAD (eg, hazard ratio [HR] per SD for higher apolipoprotein B/A‐1 ratio, 1.30; 95% CI, 1.25–1.36), but not with incident PAD (HR per SD for higher apolipoprotein B/A‐1 ratio, 1.04; 95% CI, 0.95–1.14; Pheterogeneity
Published: 2021

11. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability (Nature Communications, (2021), 12, 1, (24), 10.1038/s41467-020-19366-9)

Author: Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J.L. (Josine L.), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A.J. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), Geus, E.J.C. (Eco) de, Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), Duijn, C.M. (Cornelia) van, Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Matullo, G., Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth J. F.), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P. (Patricia), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Barroso, I.E. (Inês), Morris, A.P. (Andrew), Prokopenko, I. (Inga), Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J.L. (Josine L.), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A.J. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), Geus, E.J.C. (Eco) de, Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), Duijn, C.M. (Cornelia) van, Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Matullo, G., Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth J. F.), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P. (Patricia), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Barroso, I.E. (Inês), Morris, A.P. (Andrew), and Prokopenko, I. (Inga)
Abstract: The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.
Published: 2021
Full Text: View/download PDF

12. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J. (Josine), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah H.), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), de Geus, E.J.C.N. (Eco J. C. N.), Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard O.), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), van Duijn, C.M. (Cornelia M.), Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy L.), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Navis, G. (Gerjan), Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P.B. (Patricia B.), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Dupuis, J. (Josée), Barroso, I.E. (Inês), Morris, A.P. (Andrew P.), Prokopenko, I. (Inga), Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J. (Josine), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah H.), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), de Geus, E.J.C.N. (Eco J. C. N.), Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard O.), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), van Duijn, C.M. (Cornelia M.), Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy L.), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Navis, G. (Gerjan), Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P.B. (Patricia B.), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Dupuis, J. (Josée), Barroso, I.E. (Inês), Morris, A.P. (Andrew P.), and Prokopenko, I. (Inga)
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021
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13. Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

Author: Saarentaus, E. C. (Elmo Christian), Havulinna, A. S. (Aki Samuli), Mars, N. (Nina), Ahola-Olli, A. (Ari), Kiiskinen, T. T. (Tuomo Tapio Johannes), Partanen, J. (Juulia), Ruotsalainen, S. (Sanni), Kurki, M. (Mitja), Urpa, L. M. (Lea Martta), Chen, L. (Lei), Perola, M. (Markus), Salomaa, V. (Veikko), Veijola, J. (Juha), Männikkö, M. (Minna), Hall, I. M. (Ira M.), Pietiläinen, O. (Olli), Kaprio, J. (Jaakko), Ripatti, S. (Samuli), Daly, M. (Mark), Palotie, A. (Aarno), Saarentaus, E. C. (Elmo Christian), Havulinna, A. S. (Aki Samuli), Mars, N. (Nina), Ahola-Olli, A. (Ari), Kiiskinen, T. T. (Tuomo Tapio Johannes), Partanen, J. (Juulia), Ruotsalainen, S. (Sanni), Kurki, M. (Mitja), Urpa, L. M. (Lea Martta), Chen, L. (Lei), Perola, M. (Markus), Salomaa, V. (Veikko), Veijola, J. (Juha), Männikkö, M. (Minna), Hall, I. M. (Ira M.), Pietiläinen, O. (Olli), Kaprio, J. (Jaakko), Ripatti, S. (Samuli), Daly, M. (Mark), and Palotie, A. (Aarno)
Abstract: Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of trad
Published: 2021

14. The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease

Author: Kalaoja, M. (Marita), Corbin, L. J. (Laura J.), Tan, V. Y. (Vanessa Y.), Ahola‐Olli, A. V. (Ari V.), Havulinna, A. S. (Aki S.), Santalahti, K. (Kristiina), Pitkänen, N. (Niina), Lehtimäki, T. (Terho), Lyytikäinen, L. (Leo‐Pekka), Raitoharju, E. (Emma), Seppälä, I. (Ilkka), Kähönen, M. (Mika), Ripatti, S. (Samuli), Palotie, A. (Aarno), Perola, M. (Markus), Viikari, J. S. (Jorma S.), Jalkanen, S. (Sirpa), Maksimow, M. (Mikael), Salomaa, V. (Veikko), Salmi, M. (Marko), Raitakari, O. T. (Olli T.), Kettunen, J. (Johannes), Timpson, N. J. (Nicholas J.), Kalaoja, M. (Marita), Corbin, L. J. (Laura J.), Tan, V. Y. (Vanessa Y.), Ahola‐Olli, A. V. (Ari V.), Havulinna, A. S. (Aki S.), Santalahti, K. (Kristiina), Pitkänen, N. (Niina), Lehtimäki, T. (Terho), Lyytikäinen, L. (Leo‐Pekka), Raitoharju, E. (Emma), Seppälä, I. (Ilkka), Kähönen, M. (Mika), Ripatti, S. (Samuli), Palotie, A. (Aarno), Perola, M. (Markus), Viikari, J. S. (Jorma S.), Jalkanen, S. (Sirpa), Maksimow, M. (Mikael), Salomaa, V. (Veikko), Salmi, M. (Marko), Raitakari, O. T. (Olli T.), Kettunen, J. (Johannes), and Timpson, N. J. (Nicholas J.)
Abstract: Objective: This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease. Methods: BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI‐driven cytokines on risk of obesity‐related diseases. Results: Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein‐1 (MCP‐1), and tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08‐1.19), 1.08 (95% CI: 1.04‐1.14), and 1.13 (95% CI: 1.04‐1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00‐1.06). There was inconsistent evidence for a protective role of MCP‐1 against inflammatory bowel diseases. Conclusions: Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI‐driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.
Published: 2021

15. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author: Steinthorsdottir, V. (Valgerdur), McGinnis, R. (Ralph), Williams, N. O. (Nicholas O.), Stefansdottir, L. (Lilja), Thorleifsson, G. (Gudmar), Shooter, S. (Scott), Fadista, J. (Joao), Sigurdsson, J. K. (Jon K.), Auro, K. M. (Kirsi M.), Berezina, G. (Galina), Borges, M.-C. (Maria-Carolina), Bumpstead, S. (Suzannah), Bybjerg-Grauholm, J. (Jonas), Colgiu, I. (Irina), Dolby, V. A. (Vivien A.), Dudbridge, F. (Frank), Engel, S. M. (Stephanie M.), Franklin, C. S. (Christopher S.), Frigge, M. L. (Michael L.), Frisbaek, Y. (Yr), Geirsson, R. T. (Reynir T.), Geller, F. (Frank), Gretarsdottir, S. (Solveig), Gudbjartsson, D. F. (Daniel F.), Harmon, Q. (Quaker), Hougaard, D. M. (David Michael), Hegay, T. (Tatyana), Helgadottir, A. (Anna), Hjartardottir, S. (Sigrun), Jaeaeskelaeinen, T. (Tiina), Johannsdottir, H. (Hrefna), Jonsdottir, I. (Ingileif), Juliusdottir, T. (Thorhildur), Kalsheker, N. (Noor), Kasimov, A. (Abdumadjit), Kemp, J. P. (John P.), Kivinen, K. (Katja), Klungsoyr, K. (Kari), Lee, W. K. (Wai K.), Melbye, M. (Mads), Miedzybrodska, Z. (Zosia), Moffett, A. (Ashley), Najmutdinova, D. (Dilbar), Nishanova, F. (Firuza), Olafsdottir, T. (Thorunn), Perola, M. (Markus), Pipkin, F. B. (Fiona Broughton), Poston, L. (Lucilla), Prescott, G. (Gordon), Saevarsdottir, S. (Saedis), Salimbayeva, D. (Damilya), Scaife, P. J. (Paula Juliet), Skotte, L. (Line), Staines-Urias, E. (Eleonora), Stefansson, O. A. (Olafur A.), Sorensen, K. M. (Karina Meden), Thomsen, L. C. (Liv Cecilie Vestrheim), Tragante, V. (Vinicius), Trogstad, L. (Lill), Simpson, N. A. (Nigel A. B.), Laivuori, H. (Hannele), Morgan, L. (Linda), Aripova, T. (Tamara), Casas, J. P. (Juan P.), Dominiczak, A. F. (Anna F.), Walker, J. J. (James J.), Thorsteinsdottir, U. (Unnur), Iversen, A.-C. (Ann-Charlotte), Feenstra, B. (Bjarke), Lawlor, D. A. (Deborah A.), Boyd, H. A. (Heather Allison), Magnus, P. (Per), Zakhidova, N. (Nodira), Svyatova, G. (Gulnara), Stefansson, K. (Kari), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Pouta, A. (Anneli), Macphail, S. (Sheila), Kilby, M. (Mark), Habiba, M. (Marwan), Williamson, C. (Catherine), O'Shaughnessy, K. (Kevin), O'Brien, S. (Shaughn), Cameron, A. (Alan), Redman, C. W. (Christopher W. G.), Farrall, M. (Martin), and Caulfield, M. (Mark)
Subjects: embryonic structures, reproductive and urinary physiology, female genital diseases and pregnancy complications
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
Published: 2020

16. Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

Author: Van Zuydam, N.R. (Natalie R.), Ladenvall, C. (Claes), Voight, B.F. (Benjamin), Strawbridge, R.J. (Rona), Fernandez-Tajes, J. (Juan), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil R.), Mahajan, A. (Anubha), Vlachopoulou, E. (Efthymia), Goel, A. (Anuj), Kleber, M.E. (Marcus), Nelson, C.P. (Christopher P.), Kwee, L.C. (Lydia Coulter), Esko, T. (Tõnu), Mihailov, E. (Evelin), Mägi, R. (Reedik), Milani, L. (Lili), Fischer, K. (Krista), Kanoni, S. (Stavroula), Kumar, J. (Jitender), Song, C. (Ci), Hartiala, J.A. (Jaana A.), Pedersen, N.L. (Nancy), Perola, M. (Markus), Gieger, C. (Christian), Peters, A. (Annette), Qu, L. (Liming), Willems, S.M. (Sara), Doney, A.S.F. (Alex), Morris, A.D. (Andrew D.), Zheng, Y. (Yan), Sesti, G. (Giorgio), Hu, F.B. (Frank), Qi, L. (Lu), Laakso, M. (Markku), Thorsteinsdottir, U. (Unnur), Grallert, H. (Harald), Duijn, C.M. (Cornelia) van, Reilly, M.P. (Muredach), Ingelsson, E. (Erik), Deloukas, P. (Panos), Kathiresan, S. (Sek), Metspalu, A. (Andres), Shah, S.H. (Svati), Sinisalo, J. (Juha), Salomaa, V. (Veikko), Hamsten, A. (Anders), Samani, N.J. (Nilesh), Ye, S. (Shu), Hazen, S.L. (Stanley), Watkins, H. (Hugh), Saleheen, D. (Danish), Morris, A.P. (Andrew), Colhoun, H.M. (H.), Groop, L. (Leif), McCarthy, M.I. (Mark), Palmer, C.N.A. (Colin), Van Zuydam, N.R. (Natalie R.), Ladenvall, C. (Claes), Voight, B.F. (Benjamin), Strawbridge, R.J. (Rona), Fernandez-Tajes, J. (Juan), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil R.), Mahajan, A. (Anubha), Vlachopoulou, E. (Efthymia), Goel, A. (Anuj), Kleber, M.E. (Marcus), Nelson, C.P. (Christopher P.), Kwee, L.C. (Lydia Coulter), Esko, T. (Tõnu), Mihailov, E. (Evelin), Mägi, R. (Reedik), Milani, L. (Lili), Fischer, K. (Krista), Kanoni, S. (Stavroula), Kumar, J. (Jitender), Song, C. (Ci), Hartiala, J.A. (Jaana A.), Pedersen, N.L. (Nancy), Perola, M. (Markus), Gieger, C. (Christian), Peters, A. (Annette), Qu, L. (Liming), Willems, S.M. (Sara), Doney, A.S.F. (Alex), Morris, A.D. (Andrew D.), Zheng, Y. (Yan), Sesti, G. (Giorgio), Hu, F.B. (Frank), Qi, L. (Lu), Laakso, M. (Markku), Thorsteinsdottir, U. (Unnur), Grallert, H. (Harald), Duijn, C.M. (Cornelia) van, Reilly, M.P. (Muredach), Ingelsson, E. (Erik), Deloukas, P. (Panos), Kathiresan, S. (Sek), Metspalu, A. (Andres), Shah, S.H. (Svati), Sinisalo, J. (Juha), Salomaa, V. (Veikko), Hamsten, A. (Anders), Samani, N.J. (Nilesh), Ye, S. (Shu), Hazen, S.L. (Stanley), Watkins, H. (Hugh), Saleheen, D. (Danish), Morris, A.P. (Andrew), Colhoun, H.M. (H.), Groop, L. (Leif), McCarthy, M.I. (Mark), and Palmer, C.N.A. (Colin)
Abstract: Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
Published: 2020
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17. A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Author: Prokić, I. (Ivana), Lahousse, L. (Lies), de Vries, M. (Maaike), Liu, J. (Jun), Kalaoja, M. (Marita), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), van Diemen, C.C. (Cleo C.), Spek, A. (Ashley) van der, Zhernakova, A. (Alexandra), Fu, J. (Jingyuan), Ghanbari, M. (Mohsen), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Havulinna, A.S. (Aki), Perola, M. (Markus), Salomaa, V. (Veikko), Kao, W.H.L. (Wen), Ärnlöv, J. (Johan), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Boezen, H.M. (H Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Lahousse, L. (Lies), de Vries, M. (Maaike), Liu, J. (Jun), Kalaoja, M. (Marita), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), van Diemen, C.C. (Cleo C.), Spek, A. (Ashley) van der, Zhernakova, A. (Alexandra), Fu, J. (Jingyuan), Ghanbari, M. (Mohsen), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Havulinna, A.S. (Aki), Perola, M. (Markus), Salomaa, V. (Veikko), Kao, W.H.L. (Wen), Ärnlöv, J. (Johan), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Boezen, H.M. (H Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)
Abstract: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally i
Published: 2020
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18. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), Codd, V. (Veryan), Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), and Codd, V. (Veryan)
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Published: 2020
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19. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

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

20. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author: Surendran, P. (Praveen), Feofanova, E. V. (Elena, V), Lahrouchi, N. (Najim), Ntalla, I. (Ioanna), Karthikeyan, S. (Savita), Cook, J. (James), Chen, L. (Lingyan), Mifsud, B. (Borbala), Yao, C. (Chen), Kraja, A. T. (Aldi T.), Cartwright, J. H. (James H.), Hellwege, J. N. (Jacklyn N.), Giri, A. (Ayush), Tragante, V. (Vinicius), Thorleifsson, G. (Gudmar), Liu, D. J. (Dajiang J.), Prins, B. P. (Bram P.), Stewart, I. D. (Isobel D.), Cabrera, C. P. (Claudia P.), Eales, J. M. (James M.), Akbarov, A. (Artur), Auer, P. L. (Paul L.), Bielak, L. F. (Lawrence F.), Bis, J. C. (Joshua C.), Braithwaite, V. S. (Vickie S.), Brody, J. A. (Jennifer A.), Daw, E. W. (E. Warwick), Warren, H. R. (Helen R.), Drenos, F. (Fotios), Nielsen, S. F. (Sune Fallgaard), Faul, J. D. (Jessica D.), Fauman, E. B. (Eric B.), Fava, C. (Cristiano), Ferreira, T. (Teresa), Foley, C. N. (Christopher N.), Franceschini, N. (Nora), Gao, H. (He), Giannakopoulou, O. (Olga), Giulianini, F. (Franco), Gudbjartsson, D. F. (Daniel F.), Guo, X. (Xiuqing), Harris, S. E. (Sarah E.), Havulinna, A. S. (Aki S.), Helgadottir, A. (Anna), Huffman, J. E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Kanoni, S. (Stavroula), Kontto, J. (Jukka), Larson, M. G. (Martin G.), Li-Gao, R. (Ruifang), Lindstrom, J. (Jaana), Lotta, L. A. (Luca A.), Lu, Y. (Yingchang), Luan, J. (Jian'an), Mahajan, A. (Anubha), Malerba, G. (Giovanni), Masca, N. G. (Nicholas G. D.), Mei, H. (Hao), Menni, C. (Cristina), Mook-Kanamori, D. O. (Dennis O.), Mosen-Ansorena, D. (David), Muller-Nurasyid, M. (Martina), Pare, G. (Guillaume), Paul, D. S. (Dirk S.), Perola, M. (Markus), Poveda, A. (Alaitz), Rauramaa, R. (Rainer), Richard, M. (Melissa), Richardson, T. G. (Tom G.), Sepulveda, N. (Nuno), Sim, X. (Xueling), Smith, A. V. (Albert, V), Smith, J. A. (Jennifer A.), Staley, J. R. (James R.), Stanakova, A. (Alena), Sulem, P. (Patrick), Theriault, S. (Sebastien), Thorsteinsdottir, U. (Unnur), Trompet, S. (Stella), Varga, T. V. (Tibor V.), Edwards, D. R. (Digna R. Velez), Veronesi, G. (Giovanni), Weiss, S. (Stefan), Willems, S. M. (Sara M.), Yao, J. (Jie), Young, R. (Robin), Yu, B. (Bing), Zhang, W. (Weihua), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Evangelou, E. (Evangelos), Aeschbacher, S. (Stefanie), Asllanaj, E. (Eralda), Blankenberg, S. (Stefan), Bonnycastle, L. L. (Lori L.), Bork-Jensen, J. (Jette), Brandslund, I. (Ivan), Braund, P. S. (Peter S.), Burgess, S. (Stephen), Cho, K. (Kelly), Christensen, C. (Cramer), Connell, J. (John), de Mutsert, R. (Renee), Dominiczak, A. F. (Anna F.), Dorr, M. (Marcus), Eiriksdottir, G. (Gudny), Farmaki, A.-E. (Aliki-Eleni), Gaziano, J. M. (J. Michael), Grarup, N. (Niels), Grove, M. L. (Megan L.), Hallmans, G. (Goran), Hansen, T. (Torben), Have, C. T. (Christian T.), Heiss, G. (Gerardo), Jorgensen, M. E. (Marit E.), Jousilahti, P. (Pekka), Kajantie, E. (Eero), Kamat, M. (Mihir), Karajamaki, A. (AnneMari), Karpe, F. (Fredrik), Koistinen, H. A. (Heikki A.), Kovesdy, C. P. (Csaba P.), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Lannfelt, L. (Lars), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Linneberg, A. (Allan), Martin, L. W. (Lisa W.), Moitry, M. (Marie), Nadkarni, G. (Girish), Neville, M. J. (Matt J.), Palmer, C. N. (Colin N. A.), Papanicolaou, G. J. (George J.), Pedersen, O. (Oluf), Peters, J. (James), Poulter, N. (Neil), Rasheed, A. (Asif), Rasmussen, K. L. (Katrine L.), Rayner, N. W. (N. William), Magi, R. (Reedik), Renstrom, F. (Frida), Rettig, R. (Rainer), Rossouw, J. (Jacques), Schreiner, P. J. (Pamela J.), Sever, P. S. (Peter S.), Sigurdsson, E. L. (Emil L.), Skaaby, T. (Tea), Sun, Y. V. (Yan, V), Sundstrom, J. (Johan), Thorgeirsson, G. (Gudmundur), Esko, T. (Tonu), Trabetti, E. (Elisabetta), Tsao, P. S. (Philip S.), Tuomi, T. (Tiinamaija), Turner, S. T. (Stephen T.), Tzoulaki, I. (Ioanna), Vaartjes, I. (Ilonca), Vergnaud, A.-C. (Anne-Claire), Willer, C. J. (Cristen J.), Wilson, P. W. (Peter W. F.), Witte, D. R. (Daniel R.), Yonova-Doing, E. (Ekaterina), Zhang, H. (He), Aliya, N. (Naheed), Almgren, P. (Peter), Amouyel, P. (Philippe), Asselbergs, F. W. (Folkert W.), Barnes, M. R. (Michael R.), Blakemore, A. I. (Alexandra, I), Boehnke, M. (Michael), Bots, M. L. (Michiel L.), Bottinger, E. P. (Erwin P.), Buring, J. E. (Julie E.), Chambers, J. C. (John C.), Chen, Y. I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Conen, D. (David), Correa, A. (Adolfo), Smith, G. D. (George Davey), de Boer, R. A. (Rudolf A.), Deary, I. J. (Ian J.), Dedoussis, G. (George), Deloukas, P. (Panos), Di Angelantonio, E. (Emanuele), Elliott, P. (Paul), Felix, S. B. (Stephan B.), Ferrieres, J. (Jean), Ford, I. (Ian), Fornage, M. (Myriam), Franks, P. W. (Paul W.), Franks, S. (Stephen), Frossard, P. (Philippe), Gambaro, G. (Giovanni), Gaunt, T. R. (Tom R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Harris, T. B. (Tamara B.), Hayward, C. (Caroline), Hennig, B. J. (Branwen J.), Herzig, K.-H. (Karl-Heinz), Ingelsson, E. (Erik), Tuomilehto, J. (Jaakko), Järvelin, M.-R. (Marjo-Riitta), Jukema, J. W. (J. Wouter), Kardia, S. L. (Sharon L. R.), Kee, F. (Frank), Kooner, J. S. (Jaspal S.), Kooperberg, C. (Charles), Launer, L. J. (Lenore J.), Lind, L. (Lars), Loos, R. J. (Ruth J. F.), Majumder, A. A. (Abdulla Al Shafi), Laakso, M. (Markku), McCarthy, M. I. (Mark, I), Melander, O. (Olle), Mohlke, K. L. (Karen L.), Murray, A. D. (Alison D.), Nordestgaard, B. G. (Borge Gronne), Orho-Melander, M. (Marju), Packard, C. J. (Chris J.), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Polasek, O. (Ozren), Porteous, D. J. (David J.), Prentice, A. M. (Andrew M.), Province, M. A. (Michael A.), Relton, C. L. (Caroline L.), Rice, K. (Kenneth), Ridker, P. M. (Paul M.), Rolandsson, O. (Olov), Rosendaal, F. R. (Frits R.), Rotter, J. I. (Jerome, I), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N. J. (Nilesh J.), Sattar, N. (Naveed), Sheu, W. H. (Wayne H-H), Smith, B. H. (Blair H.), Soranzo, N. (Nicole), Spector, T. D. (Timothy D.), Starr, J. M. (John M.), Sebert, S. (Sylvain), Taylor, K. D. (Kent D.), Lakka, T. A. (Timo A.), Timpson, N. J. (Nicholas J.), Tobin, M. D. (Martin D.), van der Harst, P. (Pim), van der Meer, P. (Peter), Ramachandran, V. S. (Vasan S.), Verweij, N. (Niek), Virtamo, J. (Jarmo), Volker, U. (Uwe), Weir, D. R. (David R.), Zeggini, E. (Eleftheria), Charchar, F. J. (Fadi J.), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Tomaszewski, M. (Maciej), Butterworth, A. S. (Adam S.), Caulfield, M. J. (Mark J.), Danesh, J. (John), Edwards, T. L. (Todd L.), Holm, H. (Hilma), Hung, A. M. (Adriana M.), Lindgren, C. M. (Cecilia M.), Liu, C. (Chunyu), Manning, A. K. (Alisa K.), Morris, A. P. (Andrew P.), Morrison, A. C. (Alanna C.), O'Donnell, C. J. (Christopher J.), Psaty, B. M. (Bruce M.), Saleheen, D. (Danish), Stefansson, K. (Kari), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel, I), Levy, D. (Daniel), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), Howson, J. M. (Joanna M. M.), Surendran, P. (Praveen), Feofanova, E. V. (Elena, V), Lahrouchi, N. (Najim), Ntalla, I. (Ioanna), Karthikeyan, S. (Savita), Cook, J. (James), Chen, L. (Lingyan), Mifsud, B. (Borbala), Yao, C. (Chen), Kraja, A. T. (Aldi T.), Cartwright, J. H. (James H.), Hellwege, J. N. (Jacklyn N.), Giri, A. (Ayush), Tragante, V. (Vinicius), Thorleifsson, G. (Gudmar), Liu, D. J. (Dajiang J.), Prins, B. P. (Bram P.), Stewart, I. D. (Isobel D.), Cabrera, C. P. (Claudia P.), Eales, J. M. (James M.), Akbarov, A. (Artur), Auer, P. L. (Paul L.), Bielak, L. F. (Lawrence F.), Bis, J. C. (Joshua C.), Braithwaite, V. S. (Vickie S.), Brody, J. A. (Jennifer A.), Daw, E. W. (E. Warwick), Warren, H. R. (Helen R.), Drenos, F. (Fotios), Nielsen, S. F. (Sune Fallgaard), Faul, J. D. (Jessica D.), Fauman, E. B. (Eric B.), Fava, C. (Cristiano), Ferreira, T. (Teresa), Foley, C. N. (Christopher N.), Franceschini, N. (Nora), Gao, H. (He), Giannakopoulou, O. (Olga), Giulianini, F. (Franco), Gudbjartsson, D. F. (Daniel F.), Guo, X. (Xiuqing), Harris, S. E. (Sarah E.), Havulinna, A. S. (Aki S.), Helgadottir, A. (Anna), Huffman, J. E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Kanoni, S. (Stavroula), Kontto, J. (Jukka), Larson, M. G. (Martin G.), Li-Gao, R. (Ruifang), Lindstrom, J. (Jaana), Lotta, L. A. (Luca A.), Lu, Y. (Yingchang), Luan, J. (Jian'an), Mahajan, A. (Anubha), Malerba, G. (Giovanni), Masca, N. G. (Nicholas G. D.), Mei, H. (Hao), Menni, C. (Cristina), Mook-Kanamori, D. O. (Dennis O.), Mosen-Ansorena, D. (David), Muller-Nurasyid, M. (Martina), Pare, G. (Guillaume), Paul, D. S. (Dirk S.), Perola, M. (Markus), Poveda, A. (Alaitz), Rauramaa, R. (Rainer), Richard, M. (Melissa), Richardson, T. G. (Tom G.), Sepulveda, N. (Nuno), Sim, X. (Xueling), Smith, A. V. (Albert, V), Smith, J. A. (Jennifer A.), Staley, J. R. (James R.), Stanakova, A. (Alena), Sulem, P. (Patrick), Theriault, S. (Sebastien), Thorsteinsdottir, U. (Unnur), Trompet, S. (Stella), Varga, T. V. (Tibor V.), Edwards, D. R. (Digna R. Velez), Veronesi, G. (Giovanni), Weiss, S. (Stefan), Willems, S. M. (Sara M.), Yao, J. (Jie), Young, R. (Robin), Yu, B. (Bing), Zhang, W. (Weihua), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Evangelou, E. (Evangelos), Aeschbacher, S. (Stefanie), Asllanaj, E. (Eralda), Blankenberg, S. (Stefan), Bonnycastle, L. L. (Lori L.), Bork-Jensen, J. (Jette), Brandslund, I. (Ivan), Braund, P. S. (Peter S.), Burgess, S. (Stephen), Cho, K. (Kelly), Christensen, C. (Cramer), Connell, J. (John), de Mutsert, R. (Renee), Dominiczak, A. F. (Anna F.), Dorr, M. (Marcus), Eiriksdottir, G. (Gudny), Farmaki, A.-E. (Aliki-Eleni), Gaziano, J. M. (J. Michael), Grarup, N. (Niels), Grove, M. L. (Megan L.), Hallmans, G. (Goran), Hansen, T. (Torben), Have, C. T. (Christian T.), Heiss, G. (Gerardo), Jorgensen, M. E. (Marit E.), Jousilahti, P. (Pekka), Kajantie, E. (Eero), Kamat, M. (Mihir), Karajamaki, A. (AnneMari), Karpe, F. (Fredrik), Koistinen, H. A. (Heikki A.), Kovesdy, C. P. (Csaba P.), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Lannfelt, L. (Lars), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Linneberg, A. (Allan), Martin, L. W. (Lisa W.), Moitry, M. (Marie), Nadkarni, G. (Girish), Neville, M. J. (Matt J.), Palmer, C. N. (Colin N. A.), Papanicolaou, G. J. (George J.), Pedersen, O. (Oluf), Peters, J. (James), Poulter, N. (Neil), Rasheed, A. (Asif), Rasmussen, K. L. (Katrine L.), Rayner, N. W. (N. William), Magi, R. (Reedik), Renstrom, F. (Frida), Rettig, R. (Rainer), Rossouw, J. (Jacques), Schreiner, P. J. (Pamela J.), Sever, P. S. (Peter S.), Sigurdsson, E. L. (Emil L.), Skaaby, T. (Tea), Sun, Y. V. (Yan, V), Sundstrom, J. (Johan), Thorgeirsson, G. (Gudmundur), Esko, T. (Tonu), Trabetti, E. (Elisabetta), Tsao, P. S. (Philip S.), Tuomi, T. (Tiinamaija), Turner, S. T. (Stephen T.), Tzoulaki, I. (Ioanna), Vaartjes, I. (Ilonca), Vergnaud, A.-C. (Anne-Claire), Willer, C. J. (Cristen J.), Wilson, P. W. (Peter W. F.), Witte, D. R. (Daniel R.), Yonova-Doing, E. (Ekaterina), Zhang, H. (He), Aliya, N. (Naheed), Almgren, P. (Peter), Amouyel, P. (Philippe), Asselbergs, F. W. (Folkert W.), Barnes, M. R. (Michael R.), Blakemore, A. I. (Alexandra, I), Boehnke, M. (Michael), Bots, M. L. (Michiel L.), Bottinger, E. P. (Erwin P.), Buring, J. E. (Julie E.), Chambers, J. C. (John C.), Chen, Y. I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Conen, D. (David), Correa, A. (Adolfo), Smith, G. D. (George Davey), de Boer, R. A. (Rudolf A.), Deary, I. J. (Ian J.), Dedoussis, G. (George), Deloukas, P. (Panos), Di Angelantonio, E. (Emanuele), Elliott, P. (Paul), Felix, S. B. (Stephan B.), Ferrieres, J. (Jean), Ford, I. (Ian), Fornage, M. (Myriam), Franks, P. W. (Paul W.), Franks, S. (Stephen), Frossard, P. (Philippe), Gambaro, G. (Giovanni), Gaunt, T. R. (Tom R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Harris, T. B. (Tamara B.), Hayward, C. (Caroline), Hennig, B. J. (Branwen J.), Herzig, K.-H. (Karl-Heinz), Ingelsson, E. (Erik), Tuomilehto, J. (Jaakko), Järvelin, M.-R. (Marjo-Riitta), Jukema, J. W. (J. Wouter), Kardia, S. L. (Sharon L. R.), Kee, F. (Frank), Kooner, J. S. (Jaspal S.), Kooperberg, C. (Charles), Launer, L. J. (Lenore J.), Lind, L. (Lars), Loos, R. J. (Ruth J. F.), Majumder, A. A. (Abdulla Al Shafi), Laakso, M. (Markku), McCarthy, M. I. (Mark, I), Melander, O. (Olle), Mohlke, K. L. (Karen L.), Murray, A. D. (Alison D.), Nordestgaard, B. G. (Borge Gronne), Orho-Melander, M. (Marju), Packard, C. J. (Chris J.), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Polasek, O. (Ozren), Porteous, D. J. (David J.), Prentice, A. M. (Andrew M.), Province, M. A. (Michael A.), Relton, C. L. (Caroline L.), Rice, K. (Kenneth), Ridker, P. M. (Paul M.), Rolandsson, O. (Olov), Rosendaal, F. R. (Frits R.), Rotter, J. I. (Jerome, I), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N. J. (Nilesh J.), Sattar, N. (Naveed), Sheu, W. H. (Wayne H-H), Smith, B. H. (Blair H.), Soranzo, N. (Nicole), Spector, T. D. (Timothy D.), Starr, J. M. (John M.), Sebert, S. (Sylvain), Taylor, K. D. (Kent D.), Lakka, T. A. (Timo A.), Timpson, N. J. (Nicholas J.), Tobin, M. D. (Martin D.), van der Harst, P. (Pim), van der Meer, P. (Peter), Ramachandran, V. S. (Vasan S.), Verweij, N. (Niek), Virtamo, J. (Jarmo), Volker, U. (Uwe), Weir, D. R. (David R.), Zeggini, E. (Eleftheria), Charchar, F. J. (Fadi J.), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Tomaszewski, M. (Maciej), Butterworth, A. S. (Adam S.), Caulfield, M. J. (Mark J.), Danesh, J. (John), Edwards, T. L. (Todd L.), Holm, H. (Hilma), Hung, A. M. (Adriana M.), Lindgren, C. M. (Cecilia M.), Liu, C. (Chunyu), Manning, A. K. (Alisa K.), Morris, A. P. (Andrew P.), Morrison, A. C. (Alanna C.), O'Donnell, C. J. (Christopher J.), Psaty, B. M. (Bruce M.), Saleheen, D. (Danish), Stefansson, K. (Kari), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel, I), Levy, D. (Daniel), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), and Howson, J. M. (Joanna M. M.)
Abstract: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 x 10(⁻⁸)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets., Correction A Publisher Correction to this article was published on 16 March 2021.
Published: 2020

21. An epigenome-wide association study of metabolic syndrome and its components

Author: Nuotio, M.-L. (Marja-Liisa), Natalia Pervjakova, N. P. (Natalia Pervjakova), Joensuu, A. (Anni), Karhunen, V. (Ville), Hiekkalinna, T. (Tero), Milani, L. (Lili), Kettunen, J. (Johannes), Järvelin, M.-R. (Marjo-Riitta), Jousilahti, P. (Pekka), Metspalu, A. (Andres), Salomaa, V. (Veikko), Kristiansson, K. (Kati), Perola, M. (Markus), Nuotio, M.-L. (Marja-Liisa), Natalia Pervjakova, N. P. (Natalia Pervjakova), Joensuu, A. (Anni), Karhunen, V. (Ville), Hiekkalinna, T. (Tero), Milani, L. (Lili), Kettunen, J. (Johannes), Järvelin, M.-R. (Marjo-Riitta), Jousilahti, P. (Pekka), Metspalu, A. (Andres), Salomaa, V. (Veikko), Kristiansson, K. (Kati), and Perola, M. (Markus)
Abstract: The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP —previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10⁻⁸). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10⁻⁹) and waist circumference (P = 5.21 × 10⁻⁹). The previously identified type 2 diabetes–associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10⁻⁷). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10⁻⁸). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.
Published: 2020

22. Diabetes is associated with familial idiopathic normal pressure hydrocephalus:a case–control comparison with family members

Author: Räsänen, J. (Joel), Huovinen, J. (Joel), Korhonen, V. E. (Ville E.), Junkkari, A. (Antti), Kastinen, S. (Sami), Komulainen, S. (Simo), Oinas, M. (Minna), Avellan, C. (Cecilia), Frantzen, J. (Janek), Rinne, J. (Jaakko), Ronkainen, A. (Antti), Kauppinen, M. (Mikko), Lönnrot, K. (Kimmo), Perola, M. (Markus), Koivisto, A. M. (Anne M.), Remes, A. M. (Anne M.), Soininen, H. (Hilkka), Hiltunen, M. (Mikko), Helisalmi, S. (Seppo), Kurki, M. I. (Mitja I.), Jääskeläinen, J. E. (Juha E.), Leinonen, V. (Ville), Räsänen, J. (Joel), Huovinen, J. (Joel), Korhonen, V. E. (Ville E.), Junkkari, A. (Antti), Kastinen, S. (Sami), Komulainen, S. (Simo), Oinas, M. (Minna), Avellan, C. (Cecilia), Frantzen, J. (Janek), Rinne, J. (Jaakko), Ronkainen, A. (Antti), Kauppinen, M. (Mikko), Lönnrot, K. (Kimmo), Perola, M. (Markus), Koivisto, A. M. (Anne M.), Remes, A. M. (Anne M.), Soininen, H. (Hilkka), Hiltunen, M. (Mikko), Helisalmi, S. (Seppo), Kurki, M. I. (Mitja I.), Jääskeläinen, J. E. (Juha E.), and Leinonen, V. (Ville)
Abstract: Background: The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families. Methods: Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher’s exact test (two-tailed), the Mann–Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses. Results: Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1–12.9, p = 0.030). Conclusions: Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.
Published: 2020

23. Apolipoprotein A-I concentrations and risk of coronary artery disease:a Mendelian randomization study

Author: Karjalainen, M. K. (Minna K.), Holmes, M. V. (Michael V.), Wang, Q. (Qin), Anufrieva, O. (Olga), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Havulinna, A. S. (Aki S.), Kristiansson, K. (Kati), Salomaa, V. (Veikko), Perola, M. (Markus), Viikari, J. S. (Jorma S.), Raitakari, O. T. (Olli T.), Järvelin, M.-R. (Marjo-Riitta), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Karjalainen, M. K. (Minna K.), Holmes, M. V. (Michael V.), Wang, Q. (Qin), Anufrieva, O. (Olga), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Havulinna, A. S. (Aki S.), Kristiansson, K. (Kati), Salomaa, V. (Veikko), Perola, M. (Markus), Viikari, J. S. (Jorma S.), Raitakari, O. T. (Olli T.), Järvelin, M.-R. (Marjo-Riitta), Ala-Korpela, M. (Mika), and Kettunen, J. (Johannes)
Abstract: Background and aims: Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD). Although circulating apoA-I concentrations inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking. The aim was to assess the causal role of apoA-I using human genetics. Methods: We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations (p < 5 × 10−8) in 20,370 Finnish participants, and meta-analyzed our data with a previous GWAS of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts. Results: ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; p = 1.5 × 10−9) but not with confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98,1.30 per 1-SD higher apoA-I), which was different from the observational association. Similar findings were observed using an independent ABCA1 variant in sensitivity analysis. Conclusions: Genetic evidence fails to support a cardioprotective role for apoA-I. This is in line with the cumulative evidence showing that HDL-related phenotypes are unlikely to have a protective role in CAD.
Published: 2020

24. Data-driven multivariate population subgrouping via lipoprotein phenotypes versus apolipoprotein B in the risk assessment of coronary heart disease

Author: Ohukainen, P. (Pauli), Kuusisto, S. (Sanna), Kettunen, J. (Johannes), Perola, M. (Markus), Järvelin, M.-R. (Marjo-Riitta), Mäkinen, V.-P. (Ville-Petteri), Ala-Korpela, M. (Mika), Ohukainen, P. (Pauli), Kuusisto, S. (Sanna), Kettunen, J. (Johannes), Perola, M. (Markus), Järvelin, M.-R. (Marjo-Riitta), Mäkinen, V.-P. (Ville-Petteri), and Ala-Korpela, M. (Mika)
Abstract: Background and aims: Population subgrouping has been suggested as means to improve coronary heart disease (CHD) risk assessment. We explored here how unsupervised data-driven metabolic subgrouping, based on comprehensive lipoprotein subclass data, would work in large-scale population cohorts. Methods: We applied a self-organizing map (SOM) artificial intelligence methodology to define subgroups based on detailed lipoprotein profiles in a population-based cohort (n = 5789) and utilised the trained SOM in an independent cohort (n = 7607). We identified four SOM-based subgroups of individuals with distinct lipoprotein profiles and CHD risk and compared those to univariate subgrouping by apolipoprotein B quartiles. Results: The SOM-based subgroup with highest concentrations for non-HDL measures had the highest, and the subgroup with lowest concentrations, the lowest risk for CHD. However, apolipoprotein B quartiles produced better resolution of risk than the SOM-based subgroups and also striking dose-response behaviour. Conclusions: These results suggest that the majority of lipoprotein-mediated CHD risk is explained by apolipoprotein B-containing lipoprotein particles. Therefore, even advanced multivariate subgrouping, with comprehensive data on lipoprotein metabolism, may not advance CHD risk assessment.
Published: 2020

25. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author: Porcu, E. (Eleonora), Rueger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawusse), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A. (Anand), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M. J. (Marc Jan), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tonu), Fave, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T. (Timothy), Gharib, S. A. (Sina A.), Gibson, G. (Gregory), Heijmans, B. T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kahonen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimaki, T. (Terho), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G. W. (Grant W.), Mueler-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, B. L. (Brandon L.), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppala, I. (Ilkka), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), van Meurs, J. (Joyce), Veldink, J. H. (Jan H.), Verlouw, J. (Joost), Visscher, P. M. (Peter M.), Volker, U. (Uwe), Vosa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D. I. (Dorret I.), Bot, J. (Jan), Deelen, J. (Joris), Hofman, B. A. (Bert A.), Hottenga, J. J. (Jouke J.), Isaacs, A. (Aaron), Jhamai, P. M. (P. Mila), Kielbasa, S. M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (Rene), Mei, H. (Hailiang), Moed, M. (Matthijs), Nooren, I. (Irene), Pool, R. (Rene), Schalkwijk, C. G. (Casper G.), Slagboom, P. E. (P. Eline), Suchiman, H. E. (H. Eka D.), Swertz, M. A. (Morris A.), Tigchelaar, E. F. (Ettje F.), Uitterlinden, A. G. (Andre G.), van den Berg, L. H. (Leonard H.), van der Breggen, R. (Ruud), van der Kallen, C. J. (Carla J. H.), van Dijk, F. (Freerk), van Duijn, C. M. (Cornelia M.), van Galen, M. (Michiel), van Greevenbroek, M. M. (Marleen M. J.), van Heemst, D. (Diana), van Rooij, J. (Jeroen), Van't Hof, P. (Peter), van Zwet, E. W. (Erik. W.), Vermaat, M. (Martijn), Verbiest, M. (Michael), Verkerk, M. (Marijn), Zhernakova, D. V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F. A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltan)
Abstract: Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
Published: 2019

26. Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Author: Tabassum, R. (Rubina), Ramo, J. T. (Joel T.), Ripatti, P. (Pietari), Koskela, J. T. (Jukka T.), Kurki, M. (Mitja), Karjalainen, J. (Juha), Palta, P. (Priit), Hassan, S. (Shabbeer), Nunez-Fontarnau, J. (Javier), Kiiskinen, T. T. (Tuomo T. J.), Soderlund, S. (Sanni), Matikainen, N. (Niina), Gerl, M. J. (Mathias J.), Surma, M. A. (Michal A.), Klose, C. (Christian), Stitziel, N. O. (Nathan O.), Laivuori, H. (Hannele), Havulinna, A. S. (Aki S.), Service, S. K. (Susan K.), Salomaa, V. (Veikko), Pirinen, M. (Matti), Jauhiainen, M. (Matti), Daly, M. J. (Mark J.), Freimer, N. B. (Nelson B.), Palotie, A. (Aarno), Taskinen, M.-R. (Marja-Riitta), Simons, K. (Kai), Ripatti, S. (Samuli), Jalanko, A. (Anu), Kaprio, J. (Jaakko), Donner, K. (Kati), Kaunisto, M. (Mari), Mars, N. (Nina), Dada, A. (Alexander), Shcherban, A. (Anastasia), Ganna, A. (Andrea), Lehisto, A. (Arto), Kilpelainen, E. (Elina), Brein, G. (Georg), Awaisa, G. (Ghazal), Harju, J. (Jarmo), Parr, K. (Kalle), Parolo, P. D. (Pietro Della Briotta), Kajanne, R. (Risto), Lemmela, S. (Susanna), Sipila, T. P. (Timo P.), Sipila, T. (Tuomas), Lyhs, U. (Ulrike), Llorens, V. (Vincent), Niiranen, T. (Teemu), Kristiansson, K. (Kati), Mannikko, L. (Lotta), Jimenez, M. G. (Manuel Gonzalez), Perola, M. (Markus), Wong, R. (Regis), Kilpi, T. (Terhi), Hiekkalinna, T. (Tero), Jarvensivu, E. (Elina), Kaiharju, E. (Essi), Mattsson, H. (Hannele), Laukkanen, M. (Markku), Laiho, P. (Paivi), Lahteenmaki, S. (Sini), Sistonen, T. (Tuuli), Soini, S. (Sirpa), Ziemann, A. (Adam), Lehtonen, A. (Anne), Lertratanakul, A. (Apinya), Georgantas, B. (Bob), Riley-Gillis, B. (Bridget), Quarless, D. (Danjuma), Rahimov, F. (Fedik), Heap, G. (Graham), Jacob, H. (Howard), Waring, J. (Jeffrey), Davis, J. W. (Justin Wade), Smaoui, N. (Nizar), Popovic, R. (Relja), Esmaeeli, S. (Sahar), Waring, J. (Jeff), Matakidou, A. (Athena), Challis, B. (Ben), Close, D. (David), Petrovski, S. (Slave), Karlsson, A. (Antti), Schleutker, J. (Johanna), Pulkki, K. (Kari), Virolainen, P. (Petri), Kallio, L. (Lila), Mannermaa, A. (Arto), Heikkinen, S. (Sami), Kosma, V.-M. (Veli-Matti), Chen, C.-Y. (Chia-Yen), Runz, H. (Heiko), Liu, J. (Jimmy), Bronson, P. (Paola), John, S. (Sally), Landenpera, S. (Sanni), Eaton, S. (Susan), Zhou, W. (Wei), Hendolin, M. (Minna), Tuovila, O. (Outi), Pakkanen, R. (Raimo), Maranville, J. (Joseph), Usiskin, K. (Keith), Hochfeld, M. (Marla), Plenge, R. (Robert), Yang, R. (Robert), Biswas, S. (Shameek), Greenberg, S. (Steven), Laakkonen, E. (Eija), Kononen, J. (Juha), Paloneva, J. (Juha), Kujala, U. (Urho), Kuopio, T. (Teijo), Laukkanen, J. (Jari), Kangasniemi, E. (Eeva), Savinainen, K. (Kimmo), Laaksonen, R. (Reijo), Arvas, M. (Mikko), Ritari, J. (Jarmo), Partanen, J. (Jukka), Hyvarinen, K. (Kati), Wahlfors, T. (Tiina), Peterson, A. (Andrew), Oh, D. (Danny), Chang, D. (Diana), Teng, E. (Edmond), Strauss, E. (Erich), Kerchner, G. (Geoff), Chen, H. (Hao), Chen, H. (Hubert), Schutzman, J. (Jennifer), Michon, J. (John), Hunkapiller, J. (Julie), McCarthy, M. (Mark), Bowers, N. (Natalie), Lu, T. (Tim), Bhangale, T. (Tushar), Pulford, D. (David), Waterworth, D. (Dawn), Kulkarni, D. (Diptee), Xu, F. (Fanli), Betts, J. (Jo), Gordillo, J. E. (Jorge Esparza), Hoffman, J. (Joshua), Auro, K. (Kirsi), McCarthy, L. (Linda), Ghosh, S. (Soumitra), Ehm, M. (Meg), Pitkanen, K. (Kimmo), Makela, T. (Tomi), Loukola, A. (Anu), Joensuu, H. (Heikki), Sinisalo, J. (Juha), Eklund, K. (Kari), Aaltonen, L. (Lauri), Farkkila, M. (Martti), Carpen, O. (Olli), Kauppi, P. (Paula), Tienari, P. (Pentti), Ollila, T. (Terhi), Tuomi, T. (Tiinamaija), Meretoja, T. (Tuomo), Pitkaranta, A. (Anne), Turunen, J. (Joni), Hannula-Jouppi, K. (Katariina), Pikkarainen, S. (Sampsa), Seitsonen, S. (Sanna), Koskinen, M. (Miika), Palomaki, A. (Antti), Rinne, J. (Juha), Metsarinne, K. (Kaj), Elenius, K. (Klaus), Pirila, L. (Laura), Koulu, L. (Leena), Voutilainen, M. (Markku), Juonala, M. (Markus), Peltonen, S. (Sirkku), Aaltonen, V. (Vesa), Loboda, A. (Andrey), Podgornaia, A. (Anna), Chhibber, A. (Aparna), Chu, A. (Audrey), Fox, C. (Caroline), Diogo, D. (Dorothee), Holzinger, E. (Emily), Eicher, J. (John), Gormley, P. (Padhraig), Mehta, V. (Vinay), Wang, X. (Xulong), Kettunen, J. (Johannes), Pylkas, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Hinttala, R. (Reetta), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Mantere, T. (Tuomo), Remes, A. (Anne), Huhtakangas, J. (Johanna), Junttila, J. (Juhani), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Luodonpaa, M. (Marja), Hautala, N. (Nina), Karihtala, P. (Peeter), Kauppila, S. (Saila), Harju, T. (Terttu), Blomster, T. (Timo), Soininen, H. (Hilkka), Harvima, I. (Ilkka), Pihlajamaki, J. (Jussi), Kaarniranta, K. (Kai), Pelkonen, M. (Margit), Laakso, M. (Markku), Hiltunen, M. (Mikko), Kiviniemi, M. (Mikko), Kaipiainen-Seppanen, O. (Oili), Auvinen, P. (Paivi), Kalviainen, R. (Reetta), Julkunen, V. (Valtteri), Malarstig, A. (Anders), Hedman, A. (Asa), Marshal, C. (Catherine), Whelan, C. (Christopher), Lehtonen, H. (Heli), Parkkinen, J. (Jaakko), Linden, K. (Kari), Kalpala, K. (Kirsi), Miller, M. (Melissa), Bing, N. (Nan), McDonough, S. (Stefan), Chen, X. (Xing), Hu, X. (Xinli), Wu, Y. (Ying), Auranen, A. (Annika), Jussila, A. (Airi), Uusitalo-Jarvinen, H. (Hannele), Kankaanranta, H. (Hannu), Uusitalo, H. (Hannu), Peltola, J. (Jukka), Kahonen, M. (Mika), Isomaki, P. (Pia), Laitinen, T. (Tarja), Salmi, T. (Teea), Muslin, A. (Anthony), Wang, C. (Clarence), Chatelain, C. (Clement), Xu, E. (Ethan), Auge, F. (Franck), Call, K. (Kathy), Klinger, K. (Kathy), Crohns, M. (Marika), Gossel, M. (Matthias), Palin, K. (Kimmo), Rivas, M. (Manuel), Siirtola, H. (Harri), and Tabuenca, J. G. (Javier Gracia)
Subjects: lipids (amino acids, peptides, and proteins)
Abstract: Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P
Published: 2019

27. Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

Author: Sliz, E. (Eeva), Kalaoja, M. (Marita), Ahola-Olli, A. (Ari), Raitakari, O. (Olli), Perola, M. (Markus), Salomaa, V. (Veikko), Lehtimäki, T. (Terho), Karhu, T. (Toni), Viinamäki, H. (Heimo), Salmi, M. (Marko), Santalahti, K. (Kristiina), Jalkanen, S. (Sirpa), Jokelainen, J. (Jari), Keinänen-Kiukaanniemi, S. (Sirkka), Männikkö, M. (Minna), Herzig, K.-H. (Karl-Heinz), Järvelin, M.-R. (Marjo-Riitta), Sebert, S. (Sylvain), and Kettunen, J. (Johannes)
Abstract: Background: Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood. Objective: To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns. Methods: Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels. Results: We identified seven novel and six previously reported genetic associations (p
Published: 2019

28. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), Wilson, J.F. (James), Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), and Wilson, J.F. (James)
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019
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29. Correction: Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation (Molecular Psychiatry, (2018), 10.1038/s41380-018-0112-7)

Author: Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Cantwell, L.B. (Laura B.), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, P.K. (Paul K.), Crane, L.M.A., Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard), Goate, A. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Kunkle, B. (Brian), Perola, M. (Markus), Psaty, B.M. (Bruce), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Valladares, O. (Otto), Vardarajan, B.N. (Badri), Wang, L.S. (Li-San), Wang, W. (Weixin), Wijsman, E. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M.J. (Mark), Boerwinkle, E.A. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Martin, E.R., Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), Farrer, L.A. (Lindsay), Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Cantwell, L.B. (Laura B.), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, P.K. (Paul K.), Crane, L.M.A., Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard), Goate, A. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Kunkle, B. (Brian), Perola, M. (Markus), Psaty, B.M. (Bruce), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Valladares, O. (Otto), Vardarajan, B.N. (Badri), Wang, L.S. (Li-San), Wang, W. (Weixin), Wijsman, E. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M.J. (Mark), Boerwinkle, E.A. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Martin, E.R., Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), and Farrer, L.A. (Lindsay)
Abstract: Following publication, the authors noticed that ‘Laura Cantwell’, ‘Otto Valladares’, and ‘Li-San Wang’ were inadvertently omitted from the author list. These authors have now been added to the author list in 21st, 77th, and 79th position, respectively. This has been corrected in both the PDF and HTML versions of the article.
Published: 2019
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30. Search for Early Pancreatic Cancer Blood Biomarkers in Five European Prospective Population Biobanks Using Metabolomics

Author: Fest, J. (Jesse), Vijfhuizen, L.S. (Lisanne S.), Goeman, J.J. (Jelle), Veth, O. (Olga), Joensuu, A. (Anni), Perola, M. (Markus), Männistö, S. (Satu), Ness-Jensen, E. (Eivind), Hveem, K. (Kristian), Haller, T. (Toomas), Tonisson, N. (Neeme), Mikkel, K. (Kairit), Metspalu, A. (Andres), Duijn, C.M. (Cornelia) van, Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), Ruiter, T.R. (Rikje), Eijck, C.H.J. (Casper) van, Ommen, G.J. (Gert) van, ʼt Hoen, P.A.C. (Peter A C), Fest, J. (Jesse), Vijfhuizen, L.S. (Lisanne S.), Goeman, J.J. (Jelle), Veth, O. (Olga), Joensuu, A. (Anni), Perola, M. (Markus), Männistö, S. (Satu), Ness-Jensen, E. (Eivind), Hveem, K. (Kristian), Haller, T. (Toomas), Tonisson, N. (Neeme), Mikkel, K. (Kairit), Metspalu, A. (Andres), Duijn, C.M. (Cornelia) van, Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), Ruiter, T.R. (Rikje), Eijck, C.H.J. (Casper) van, Ommen, G.J. (Gert) van, and ʼt Hoen, P.A.C. (Peter A C)
Abstract: Most patients with pancreatic cancer present with advanced disease and die within the first year after diagnosis. Predictive biomarkers that signal the presence of pancreatic cancer in an early stage are desperately needed. We aimed to identify new and validate previously found plasma metabolomic biomarkers associated with early stages of pancreatic cancer. Prediagnostic blood samples from individuals who were to receive a diagnosis of pancreatic
Published: 2019
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31. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals

Author: Deelen, J. (Joris), Kettunen, J. (Johannes), Fischer, K. (Krista), Spek, A. (Ashley) van der, Trompet, S. (Stella), Kastenmuller, G. (Gabi), Boyd, A. (Andy), Zierer, J. (Jonas), Akker, E.B. (Erik) van den, Ala-Korpela, M. (Mika), Amin, N. (Najaf), Demirkan, A. (Ayse), Ghanbari, M. (Mohsen), Heemst, D. (Diana) van, Ikram, M.A. (Arfan), Klinken, J.B. (Jan Bert) van, Mooijaart, S.P. (Simon), Peters, A. (Annette), Salomaa, V. (Veikko), Sattar, N. (Naveed), Spector, T.D. (Timothy), Tiemeier, H.W. (Henning), Verhoeven, A. (Aswin), Waldenberger, M. (Melanie), Würtz, P. (Peter), Davey Smith, G. (George), Metspalu, A. (Andres), Perola, M. (Markus), Menni, C. (Cristina), Geleijnse, J.M. (Johanna M.), Drenos, F. (Fotios), Beekman, M. (Marian), Jukema, J.W. (Jan Wouter), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Deelen, J. (Joris), Kettunen, J. (Johannes), Fischer, K. (Krista), Spek, A. (Ashley) van der, Trompet, S. (Stella), Kastenmuller, G. (Gabi), Boyd, A. (Andy), Zierer, J. (Jonas), Akker, E.B. (Erik) van den, Ala-Korpela, M. (Mika), Amin, N. (Najaf), Demirkan, A. (Ayse), Ghanbari, M. (Mohsen), Heemst, D. (Diana) van, Ikram, M.A. (Arfan), Klinken, J.B. (Jan Bert) van, Mooijaart, S.P. (Simon), Peters, A. (Annette), Salomaa, V. (Veikko), Sattar, N. (Naveed), Spector, T.D. (Timothy), Tiemeier, H.W. (Henning), Verhoeven, A. (Aswin), Waldenberger, M. (Melanie), Würtz, P. (Peter), Davey Smith, G. (George), Metspalu, A. (Andres), Perola, M. (Markus), Menni, C. (Cristina), Geleijnse, J.M. (Johanna M.), Drenos, F. (Fotios), Beekman, M. (Marian), Jukema, J.W. (Jan Wouter), Duijn, C.M. (Cornelia) van, and Slagboom, P.E. (Eline)
Abstract: Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18–109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.
Published: 2019
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32. Associations of autozygosity with a broad range of human phenotypes

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

33. Genetic determinants of circulating glycine levels and risk of coronary artery disease

Author: Jia, Q. (Qiong), Han, Y. (Yi), Huang, P. (Pin), Woodward, N. C. (Nicholas C.), Gukasyan, J. (Janet), Kettunen, J. (Johannes), Ala‐Korpela, M. (Mika), Anufrieva, O. (Olga), Wang, Q. (Qin), Perola, M. (Markus), Raitakari, O. (Olli), Lehtimäki, T. (Terho), Viikari, J. (Jorma), Järvelin, M. (Marjo‐Riitta), Boehnke, M. (Michael), Laakso, M. (Markku), Mohlke, K. L. (Karen L.), Fiehn, O. (Oliver), Wang, Z. (Zeneng), Tang, W. W. (W.H. Wilson), Hazen, S. L. (Stanley L.), Hartiala, J. A. (Jaana A.), Allayee, H. (Hooman), Jia, Q. (Qiong), Han, Y. (Yi), Huang, P. (Pin), Woodward, N. C. (Nicholas C.), Gukasyan, J. (Janet), Kettunen, J. (Johannes), Ala‐Korpela, M. (Mika), Anufrieva, O. (Olga), Wang, Q. (Qin), Perola, M. (Markus), Raitakari, O. (Olli), Lehtimäki, T. (Terho), Viikari, J. (Jorma), Järvelin, M. (Marjo‐Riitta), Boehnke, M. (Michael), Laakso, M. (Markku), Mohlke, K. L. (Karen L.), Fiehn, O. (Oliver), Wang, Z. (Zeneng), Tang, W. W. (W.H. Wilson), Hazen, S. L. (Stanley L.), Hartiala, J. A. (Jaana A.), and Allayee, H. (Hooman)
Abstract: Background: Recent studies have revealed sexually dimorphic associations between the carbamoyl‐phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease (CAD) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl‐phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results: We sought to identify additional genetic determinants of circulating glycine levels by carrying out a meta‐analysis of genome‐wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine‐associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism (ACADM,PHGDH,COX18‐ADAMTS3,PSPH,TRIB1,PTPRD, and ABO). Glycine‐raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD. However, these effects could not be attributed directly to glycine because of associations with other CAD‐related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity‐related traits. Conclusions: These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.
Published: 2019

34. Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition

Author: Kettunen, J. (Johannes), Holmes, M. V. (Michael V.), Allara, E. (Elias), Anufrieva, O. (Olga), Ohukainen, P. (Pauli), Oliver-Williams, C. (Clare), Wang, Q. (Qin), Tillin, T. (Therese), Hughes, A. D. (Alun D.), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Viikari, J. (Jorma), Raitakari, O. T. (Olli T.), Salomaa, V. (Veikko), Järvelin, M.-R. (Marjo-Riitta), Perola, M. (Markus), Smith, G. D. (George Davey), Chaturvedi, N. (Nish), Danesh, J. (John), Di Angelantonio, E. (Emanuele), Butterworth, A. S. (Adam S.), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Holmes, M. V. (Michael V.), Allara, E. (Elias), Anufrieva, O. (Olga), Ohukainen, P. (Pauli), Oliver-Williams, C. (Clare), Wang, Q. (Qin), Tillin, T. (Therese), Hughes, A. D. (Alun D.), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Viikari, J. (Jorma), Raitakari, O. T. (Olli T.), Salomaa, V. (Veikko), Järvelin, M.-R. (Marjo-Riitta), Perola, M. (Markus), Smith, G. D. (George Davey), Chaturvedi, N. (Nish), Danesh, J. (John), Di Angelantonio, E. (Emanuele), Butterworth, A. S. (Adam S.), and Ala-Korpela, M. (Mika)
Abstract: Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18–26 nm) (−0.02 SD LDL defined by particle size; 95% CI: −0.10 to 0.05 for CETP versus −0.24 SD, 95% CI −0.30 to −0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cho
Published: 2019

35. Elevated serum alpha-1 antitrypsin is a major component of GlycA-associated risk for future morbidity and mortality

Author: Ritchie, S. C. (Scott C.), Kettunen, J. (Johannes), Brozynska, M. (Marta), Nath, A. P. (Artika P.), Havulinna, A. S. (Aki S.), Männistö, S. (Satu), Perola, M. (Markus), Salomaa, V. (Veikko), Ala-Korpela, M. (Mika), Abraham, G. (Gad), Würtz, P. (Peter), Inouye, M. (Michael), Ritchie, S. C. (Scott C.), Kettunen, J. (Johannes), Brozynska, M. (Marta), Nath, A. P. (Artika P.), Havulinna, A. S. (Aki S.), Männistö, S. (Satu), Perola, M. (Markus), Salomaa, V. (Veikko), Ala-Korpela, M. (Mika), Abraham, G. (Gad), Würtz, P. (Peter), and Inouye, M. (Michael)
Abstract: Background: GlycA is a nuclear magnetic resonance (NMR) spectroscopy biomarker that predicts risk of disease from myriad causes. It is heterogeneous; arising from five circulating glycoproteins with dynamic concentrations: alpha-1 antitrypsin (AAT), alpha-1-acid glycoprotein (AGP), haptoglobin (HP), transferrin (TF), and alpha-1-antichymotrypsin (AACT). The contributions of each glycoprotein to the disease and mortality risks predicted by GlycA remain unknown. Methods: We trained imputation models for AAT, AGP, HP, and TF from NMR metabolite measurements in 626 adults from a population cohort with matched NMR and immunoassay data. Levels of AAT, AGP, and HP were estimated in 11,861 adults from two population cohorts with eight years of follow-up, then each biomarker was tested for association with all common endpoints. Whole blood gene expression data was used to identify cellular processes associated with elevated AAT. Results: Accurate imputation models were obtained for AAT, AGP, and HP but not for TF. While AGP had the strongest correlation with GlycA, our analysis revealed variation in imputed AAT levels was the most predictive of morbidity and mortality for the widest range of diseases over the eight year follow-up period, including heart failure (meta-analysis hazard ratio = 1.60 per standard deviation increase of AAT, P-value = 1×10−10), influenza and pneumonia (HR = 1.37, P = 6×10−10), and liver diseases (HR = 1.81, P = 1×10−6). Transcriptional analyses revealed association of elevated AAT with diverse inflammatory immune pathways. Conclusions: This study clarifies the molecular underpinnings of the GlycA biomarker’s associated disease risk, and indicates a previously unrecognised association between elevated AAT and severe disease onset and mortality.
Published: 2019

36. Circulating metabolites and the risk of type 2 diabetes:a prospective study of 11,896 young adults from four Finnish cohorts

Author: Ahola-Olli, A. V. (Ari V.), Mustelin, L. (Linda), Kalimeri, M. (Maria), Kettunen, J. (Johannes), Jokelainen, J. (Jari), Auvinen, J. (Juha), Puukka, K. (Katri), Havulinna, A. S. (Aki S.), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Juonala, M. (Markus), Keinänen-Kiukaanniem, S. (Sirkka), Salomaa, V. (Veikko), Perola, M. (Markus), Järvelin, M.-R. (Marjo-Riitta), Ala-Korpela, M. (Mika), Raitakari, O. (Olli), Würtz, P. (Peter), Ahola-Olli, A. V. (Ari V.), Mustelin, L. (Linda), Kalimeri, M. (Maria), Kettunen, J. (Johannes), Jokelainen, J. (Jari), Auvinen, J. (Juha), Puukka, K. (Katri), Havulinna, A. S. (Aki S.), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Juonala, M. (Markus), Keinänen-Kiukaanniem, S. (Sirkka), Salomaa, V. (Veikko), Perola, M. (Markus), Järvelin, M.-R. (Marjo-Riitta), Ala-Korpela, M. (Mika), Raitakari, O. (Olli), and Würtz, P. (Peter)
Abstract: Aims/hypothesis: Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case−control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods: NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24–45 years). Associations between baseline metabolites and risk of developing diabetes during 8–15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results: Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59–1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31–1.33) and triacylglycerol within VLDL particles (OR 1.33–1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation: Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.
Published: 2019

37. Genetic variants in SGLT1, glucose tolerance, and cardiometabolic risk

Author: Seidelmann, S. B. (Sara B.), Feofanova, E. (Elena), Yu, B. (Bing), Franceschini, N. (Nora), Claggett, B. (Brian), Kuokkanen, M. (Mikko), Puolijoki, H. (Hannu), Ebeling, T. (Tapani), Perola, M. (Markus), Salomaa, V. (Veikko), Shah, A. (Amil), Coresh, J. (Josef), Selvin, E. (Elizabeth), MacRae, C. A. (Calum A.), Cheng, S. (Susan), Boerwinkle, E. (Eric), Solomon, S. D. (Scott D.), Seidelmann, S. B. (Sara B.), Feofanova, E. (Elena), Yu, B. (Bing), Franceschini, N. (Nora), Claggett, B. (Brian), Kuokkanen, M. (Mikko), Puolijoki, H. (Hannu), Ebeling, T. (Tapani), Perola, M. (Markus), Salomaa, V. (Veikko), Shah, A. (Amil), Coresh, J. (Josef), Selvin, E. (Elizabeth), MacRae, C. A. (Calum A.), Cheng, S. (Susan), Boerwinkle, E. (Eric), and Solomon, S. D. (Scott D.)
Abstract: Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). Conclusions: Functionally damaging missense v
Published: 2018

38. Erratum to: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Evangelou, E. (Evangelos), Warren, H. (Helen), Mosen-Ansorena, D. (David), Mifsud, B. (Borbala), Pazoki, R. (Raha), Gao, H. (He), Ntritsos, G. (Georgios), Dimou, N. (Niki), Cabrera, C.P. (Claudia P.), Karaman, I. (Ibrahim), Ng, F.L. (Fu Liang), Evangelou, M. (Marina), Witkowska, K. (Katarzyna), Tzanis, E. (Evan), Hellwege, J.N. (Jacklyn N.), Giri, A. (Ayush), Velez Edwards, D.R. (Digna R.), Sun, Y.V. (Yan V.), Cho, K. (Kelly), Gaziano, J.M. (J. Michael), Wilson, P.W.F. (Peter W. F.), Tsao, P.S. (Philip S.), Kovesdy, C.P. (Csaba P.), Esko, T. (Tonu), Mägi, R. (Reedik), Milani, L. (Lili), Almgren, P. (Peter), Boutin, T. (Thibaud), Debette, S. (Stéphanie), Ding, J. (Jun), Giulianini, F. (Franco), Holliday, E.G. (Elizabeth), Jackson, A.U. (Anne), Li-Gao, R. (Ruifang), Lin, W.-Y. (Wei-Yu), Luan, J., Mangino, M. (Massimo), Oldmeadow, C. (Christopher), Prins, B.P. (Bram Peter), Qian, Y. (Yong), Sargurupremraj, M. (Muralidharan), Shah, N. (Nisha), Surendran, P. (Praveen), Thériault, S. (Sébastien), Verweij, N. (Niek), Willems, S.M. (Sara), Zhao, J.-H. (Jing-Hua), Amouyel, P. (Philippe), Connell, J. (John), Mutsert, R. (Reneé) de, Doney, A.S.F. (Alex), Farrall, M. (Martin), Menni, C. (Cristina), Morris, A.D. (Andrew), Noordam, R. (Raymond), Pare, G. (Guillame), Poulter, N.R. (Neil), Shields, D.C. (Denis C.), Stanton, A. (Alice), McG Thom, S.A., Abecasis, G. (Gonçalo), Amin, N. (Najaf), Arking, D.E. (Dan), Ayers, K.L. (Kristin), Barbieri, C.M. (Caterina M.), Batini, C. (Chiara), Bis, J.C. (Joshua), Blake, T. (Tineka), Bochud, M. (Murielle), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boomsma, D.I. (Dorret I.), Bottinger, E.P. (Erwin P.), Braund, P.S. (Peter), Brumat, M. (Marco), Campbell, A. (Archie), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chambers, J.C. (John C.), Chauhan, G. (Ganesh), Ciullo, M. (Marina), Cocca, M. (Massimiliano), Collins, F. (Francis), Cordell, H.J. (Heather), Davies, G. (Gail), de Borst, M.H. (Martin H.), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Deelen, J. (Joris), Del Greco M, F. (Fabiola), Demirkale, C.Y. (Cumhur Yusuf), Dörr, M. (Marcus), Ehret, G.B. (Georg B.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erzurumluoglu, A.M. (A. Mesut), Ferreira, T. (Teresa), Frånberg, M. (Mattias), Franco, O.H. (Oscar), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Gieger, C. (Christian), Girotto, G. (Giorgia), Goel, A. (Anuj), Gow, A.J. (Alan J.), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Harris, S.E. (Sarah), Hartman, C.A. (Catharina A.), Havulinna, A.S. (Aki), Hicks, A.A. (Andrew A.), Hofer, E. (Edith), Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Ingelsson, E. (Erik), James, A. (Alan), Jansen, R. (Rick), Jarvelin, M.-R. (Marjo-Riitta), Joehanes, R. (Roby), Johansson, A. (Åsa), Johnson, A.D. (Andrew), Joshi, P.K. (Peter K.), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Keavney, B.D. (Bernard D.), Khaw, K.-T. (Kay-Tee), Knekt, P., Knight, J. (Joanne), Kolcic, I. (Ivana), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Laan, M. (Maris), Larson, M.G. (Martin), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David C. M.), Lin, L. (Li), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lopez, L.M. (Lorna), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Mamasoula, C. (Chrysovalanto), Marrugat, J. (Jaume), Marten, J. (Jonathan), Milaneschi, Y. (Yuri), Morgan, A. (Anna), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Munson, P.J. (Peter), Nalls, M.A. (Michael), Nandakumar, P. (Priyanka), Nelson, C.P. (Christopher P.), Niiranen, T. (Teemu), Nolte, I.M. (Ilja), Nutile, T. (Teresa), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), O’Reilly, P.F. (Paul F.), Org, E. (Elin), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Palotie, A. (Aarno), Pattie, A. (Alison), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Nguyen, Q.T. (Quang Tri), Raitakari, O. (Olli), Ren, M. (Meixia), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Ridker, P.M. (Paul), Ried, J.S. (Janina S.), Riese, H. (Harriëtte), Ripatti, S. (Samuli), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruggiero, D., Saba, Y. (Yasaman), Sala, C. (Cinzia), Salomaa, V. (Veikko), Samani, N.J. (Nilesh J.), Sarin, A.-P., Schmidt, R. (Reinhold), Schmidt, H. (Helena), Shrine, N.R.G. (Nick), Siscovick, D. (David), Smith, A.V. (Albert), Snieder, H. (Harold), Sõber, S. (Siim), Sorice, R., Starr, J.M. (John), Stott, D.J. (David. J.), Strachan, D.P. (David), Strawbridge, R.J. (Rona), Sundström, J. (Johan), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Teumer, A. (Alexander), Tobin, M.D. (Martin), Tomaszewski, M. (Maciej), Toniolo, D. (Daniela), Traglia, M. (Michela), Trompet, S. (Stella), Tuomilehto, J. (Jaakko), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vaez, A. (Ahmad), Most, P.J. (Peter) van der, Duijn, C.M. (Cornelia) van, Vergnaud, A.-C. (Anne-Claire), Verwoert, G.C. (Germaine C.), Vitart, V. (Veronique), Völker, U. (Uwe), Vollenweider, P. (Peter), Vuckovic, D. (Dragana), Watkins, H. (Hugh), Wild, S.H. (Sarah), Willemsen, G. (Gonneke), Wilson, J.F. (James F.), Wright, A.F. (Alan), Yao, J. (Jie), Zemunik, T. (Tatijana), Zhang, W. (Weihua), Attia, J. (John), Butterworth, A.S. (Adam S.), Chasman, D.I. (Daniel), Conen, D. (David), Cucca, F. (Francesco), Danesh, J. (John), Hayward, C. (Caroline), Howson, J.M.M. (Joanna M. M.), Laakso, M. (Markku), Lakatta, E.G. (Edward G.), Langenberg, C. (Claudia), Melander, O. (Olle), Mook-Kanamori, D.O. (Dennis O.), Palmer, C.N.A. (Colin N. A.), Risch, L. (Lorenz), Scott, R.A. (Robert), Scott, R.J. (Rodney J.), Sever, P. (Peter), Spector, T.D. (Timothy), van der Harst, P. (Pim), Wareham, N.J. (Nick), Zeggini, E. (Eleftheria), Levy, D. (Daniel), Munroe, P. (Patricia), Newton-Cheh, C. (Christopher), Brown, M.J. (Morris), Metspalu, A. (Andres), Hung, A.M. (Adriana M.), Ódonnell, C.J. (Christopher), Edwards, T.L. (Todd L.), Psaty, B.M. (Bruce), Tzoulaki, I., Barnes, M.J. (Michael), Wain, L.V. (Louise V.), Elliott, P. (Paul), Caulfield, M. (Mark), Evangelou, E. (Evangelos), Warren, H. (Helen), Mosen-Ansorena, D. (David), Mifsud, B. (Borbala), Pazoki, R. (Raha), Gao, H. (He), Ntritsos, G. (Georgios), Dimou, N. (Niki), Cabrera, C.P. (Claudia P.), Karaman, I. (Ibrahim), Ng, F.L. (Fu Liang), Evangelou, M. (Marina), Witkowska, K. (Katarzyna), Tzanis, E. (Evan), Hellwege, J.N. (Jacklyn N.), Giri, A. (Ayush), Velez Edwards, D.R. (Digna R.), Sun, Y.V. (Yan V.), Cho, K. (Kelly), Gaziano, J.M. (J. Michael), Wilson, P.W.F. (Peter W. F.), Tsao, P.S. (Philip S.), Kovesdy, C.P. (Csaba P.), Esko, T. (Tonu), Mägi, R. (Reedik), Milani, L. (Lili), Almgren, P. (Peter), Boutin, T. (Thibaud), Debette, S. (Stéphanie), Ding, J. (Jun), Giulianini, F. (Franco), Holliday, E.G. (Elizabeth), Jackson, A.U. (Anne), Li-Gao, R. (Ruifang), Lin, W.-Y. (Wei-Yu), Luan, J., Mangino, M. (Massimo), Oldmeadow, C. (Christopher), Prins, B.P. (Bram Peter), Qian, Y. (Yong), Sargurupremraj, M. (Muralidharan), Shah, N. (Nisha), Surendran, P. (Praveen), Thériault, S. (Sébastien), Verweij, N. (Niek), Willems, S.M. (Sara), Zhao, J.-H. (Jing-Hua), Amouyel, P. (Philippe), Connell, J. (John), Mutsert, R. (Reneé) de, Doney, A.S.F. (Alex), Farrall, M. (Martin), Menni, C. (Cristina), Morris, A.D. (Andrew), Noordam, R. (Raymond), Pare, G. (Guillame), Poulter, N.R. (Neil), Shields, D.C. (Denis C.), Stanton, A. (Alice), McG Thom, S.A., Abecasis, G. (Gonçalo), Amin, N. (Najaf), Arking, D.E. (Dan), Ayers, K.L. (Kristin), Barbieri, C.M. (Caterina M.), Batini, C. (Chiara), Bis, J.C. (Joshua), Blake, T. (Tineka), Bochud, M. (Murielle), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boomsma, D.I. (Dorret I.), Bottinger, E.P. (Erwin P.), Braund, P.S. (Peter), Brumat, M. (Marco), Campbell, A. (Archie), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chambers, J.C. (John C.), Chauhan, G. (Ganesh), Ciullo, M. (Marina), Cocca, M. (Massimiliano), Collins, F. (Francis), Cordell, H.J. (Heather), Davies, G. (Gail), de Borst, M.H. (Martin H.), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Deelen, J. (Joris), Del Greco M, F. (Fabiola), Demirkale, C.Y. (Cumhur Yusuf), Dörr, M. (Marcus), Ehret, G.B. (Georg B.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erzurumluoglu, A.M. (A. Mesut), Ferreira, T. (Teresa), Frånberg, M. (Mattias), Franco, O.H. (Oscar), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Gieger, C. (Christian), Girotto, G. (Giorgia), Goel, A. (Anuj), Gow, A.J. (Alan J.), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Harris, S.E. (Sarah), Hartman, C.A. (Catharina A.), Havulinna, A.S. (Aki), Hicks, A.A. (Andrew A.), Hofer, E. (Edith), Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Ingelsson, E. (Erik), James, A. (Alan), Jansen, R. (Rick), Jarvelin, M.-R. (Marjo-Riitta), Joehanes, R. (Roby), Johansson, A. (Åsa), Johnson, A.D. (Andrew), Joshi, P.K. (Peter K.), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Keavney, B.D. (Bernard D.), Khaw, K.-T. (Kay-Tee), Knekt, P., Knight, J. (Joanne), Kolcic, I. (Ivana), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Laan, M. (Maris), Larson, M.G. (Martin), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David C. M.), Lin, L. (Li), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lopez, L.M. (Lorna), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Mamasoula, C. (Chrysovalanto), Marrugat, J. (Jaume), Marten, J. (Jonathan), Milaneschi, Y. (Yuri), Morgan, A. (Anna), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Munson, P.J. (Peter), Nalls, M.A. (Michael), Nandakumar, P. (Priyanka), Nelson, C.P. (Christopher P.), Niiranen, T. (Teemu), Nolte, I.M. (Ilja), Nutile, T. (Teresa), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), O’Reilly, P.F. (Paul F.), Org, E. (Elin), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Palotie, A. (Aarno), Pattie, A. (Alison), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Nguyen, Q.T. (Quang Tri), Raitakari, O. (Olli), Ren, M. (Meixia), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Ridker, P.M. (Paul), Ried, J.S. (Janina S.), Riese, H. (Harriëtte), Ripatti, S. (Samuli), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruggiero, D., Saba, Y. (Yasaman), Sala, C. (Cinzia), Salomaa, V. (Veikko), Samani, N.J. (Nilesh J.), Sarin, A.-P., Schmidt, R. (Reinhold), Schmidt, H. (Helena), Shrine, N.R.G. (Nick), Siscovick, D. (David), Smith, A.V. (Albert), Snieder, H. (Harold), Sõber, S. (Siim), Sorice, R., Starr, J.M. (John), Stott, D.J. (David. J.), Strachan, D.P. (David), Strawbridge, R.J. (Rona), Sundström, J. (Johan), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Teumer, A. (Alexander), Tobin, M.D. (Martin), Tomaszewski, M. (Maciej), Toniolo, D. (Daniela), Traglia, M. (Michela), Trompet, S. (Stella), Tuomilehto, J. (Jaakko), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vaez, A. (Ahmad), Most, P.J. (Peter) van der, Duijn, C.M. (Cornelia) van, Vergnaud, A.-C. (Anne-Claire), Verwoert, G.C. (Germaine C.), Vitart, V. (Veronique), Völker, U. (Uwe), Vollenweider, P. (Peter), Vuckovic, D. (Dragana), Watkins, H. (Hugh), Wild, S.H. (Sarah), Willemsen, G. (Gonneke), Wilson, J.F. (James F.), Wright, A.F. (Alan), Yao, J. (Jie), Zemunik, T. (Tatijana), Zhang, W. (Weihua), Attia, J. (John), Butterworth, A.S. (Adam S.), Chasman, D.I. (Daniel), Conen, D. (David), Cucca, F. (Francesco), Danesh, J. (John), Hayward, C. (Caroline), Howson, J.M.M. (Joanna M. M.), Laakso, M. (Markku), Lakatta, E.G. (Edward G.), Langenberg, C. (Claudia), Melander, O. (Olle), Mook-Kanamori, D.O. (Dennis O.), Palmer, C.N.A. (Colin N. A.), Risch, L. (Lorenz), Scott, R.A. (Robert), Scott, R.J. (Rodney J.), Sever, P. (Peter), Spector, T.D. (Timothy), van der Harst, P. (Pim), Wareham, N.J. (Nick), Zeggini, E. (Eleftheria), Levy, D. (Daniel), Munroe, P. (Patricia), Newton-Cheh, C. (Christopher), Brown, M.J. (Morris), Metspalu, A. (Andres), Hung, A.M. (Adriana M.), Ódonnell, C.J. (Christopher), Edwards, T.L. (Todd L.), Psaty, B.M. (Bruce), Tzoulaki, I., Barnes, M.J. (Michael), Wain, L.V. (Louise V.), Elliott, P. (Paul), and Caulfield, M. (Mark)
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018
Full Text: View/download PDF

39. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Author: Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), Farrer, L.A. (Lindsay), Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), and Farrer, L.A. (Lindsay)
Abstract: The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 contro
Published: 2018
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40. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Author: Xue, A. (Angli), Wu, Y. (Yang), Zhu, Z. (Zhihong), Zhang, F. (Futao), Kemper, K.E. (Kathryn E.), Zheng, Z. (Zhili), Yengo, L. (Loic), Lloyd-Jones, L.R. (Luke R.), Sidorenko, J. (Julia), Wu, Y. (Yeda), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M.J. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), McRae, A.F. (Allan F.), Visscher, P.M. (Peter), Zeng, J. (Jian), Yang, J. (Jian), Xue, A. (Angli), Wu, Y. (Yang), Zhu, Z. (Zhihong), Zhang, F. (Futao), Kemper, K.E. (Kathryn E.), Zheng, Z. (Zhili), Yengo, L. (Loic), Lloyd-Jones, L.R. (Luke R.), Sidorenko, J. (Julia), Wu, Y. (Yeda), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M.J. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), McRae, A.F. (Allan F.), Visscher, P.M. (Peter), Zeng, J. (Jian), and Yang, J. (Jian)
Abstract: Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.
Published: 2018
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41. Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Author: Tynkkynen, J. (Juho), Chouraki, V. (Vincent), Lee, S.J. (Sven) van der, Hernesniemi, J. (Jussi), Yang, Q. (Qiong), Li, S. (Shuo), Beiser, A. (Alexa), Larson, M.G. (Martin), Sääksjärvi, K. (K.), Shipley, M.J., Singh-Manoux, A. (Archana), Gerszten, R.E. (Robert E.), Wang, T.J. (Thomas J.), Havulinna, A.S. (Aki), Würtz, P. (Peter), Fischer, K. (Krista), Demirkan, A. (Ayşe), Ikram, M.K. (Kamran), Amin, N. (Najaf), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Perola, M. (Markus), Metspalu, A. (Andres), Kangas, A.J. (Antti), Soininen, P. (Pasi), Ala-Korpela, M. (Mika), Vasan, R. (Ramachandran), Kivimaki, M. (Mika), Duijn, C.M. (Cornelia) van, Seshadri, S. (Sudha), Salomaa, V. (Veikko), Tynkkynen, J. (Juho), Chouraki, V. (Vincent), Lee, S.J. (Sven) van der, Hernesniemi, J. (Jussi), Yang, Q. (Qiong), Li, S. (Shuo), Beiser, A. (Alexa), Larson, M.G. (Martin), Sääksjärvi, K. (K.), Shipley, M.J., Singh-Manoux, A. (Archana), Gerszten, R.E. (Robert E.), Wang, T.J. (Thomas J.), Havulinna, A.S. (Aki), Würtz, P. (Peter), Fischer, K. (Krista), Demirkan, A. (Ayşe), Ikram, M.K. (Kamran), Amin, N. (Najaf), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Perola, M. (Markus), Metspalu, A. (Andres), Kangas, A.J. (Antti), Soininen, P. (Pasi), Ala-Korpela, M. (Mika), Vasan, R. (Ramachandran), Kivimaki, M. (Mika), Duijn, C.M. (Cornelia) van, Seshadri, S. (Sudha), and Salomaa, V. (Veikko)
Abstract: Introduction: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. Methods: We studied eight prospective cohorts with 22,623 participants profiled by nu
Published: 2018
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42. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood

Author: Qi, T. (Ting), Wu, Y. (Yang), Zeng, J. (Jian), Zhang, F. (Futao), Xue, A. (Angli), Jiang, L. (Longda), Zhu, Z. (Zhihong), Kemper, K. (Kathryn), Yengo, L. (Loic), Zheng, Z. (Zhili), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D.I. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), Marioni, R.E. (Riccardo), Montgomery, G.W. (Grant W.), Deary, I.J. (Ian), Wray, N.R. (Naomi R.), Visscher, P.M. (Peter), McRae, A.F. (Allan F.), Yang, J. (Jian), Qi, T. (Ting), Wu, Y. (Yang), Zeng, J. (Jian), Zhang, F. (Futao), Xue, A. (Angli), Jiang, L. (Longda), Zhu, Z. (Zhihong), Kemper, K. (Kathryn), Yengo, L. (Loic), Zheng, Z. (Zhili), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D.I. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), Marioni, R.E. (Riccardo), Montgomery, G.W. (Grant W.), Deary, I.J. (Ian), Wray, N.R. (Naomi R.), Visscher, P.M. (Peter), McRae, A.F. (Allan F.), and Yang, J. (Jian)
Abstract: Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b = 0.70 for cis-eQTLs and r ^ b = 0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.
Published: 2018
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43. Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

Author: Sliz, E. (Eeva), Kettunen, J. (Johannes), Holmes, M. V. (Michael V.), Williams, C. O. (Clare Oliver), Boachie, C. (Charles), Wang, Q. (Qin), Maennikkoe, M. (Minna), Sebert, S. (Sylvain), Walters, R. (Robin), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Clarke, R. (Robert), Li, L. (Liming), Rankin, N. (Naomi), Welsh, P. (Paul), Delles, C. (Christian), Jukema, J. W. (J. Wouter), Trompet, S. (Stella), Ford, I. (Ian), Perola, M. (Markus), Salomaa, V. (Veikko), Jaervelin, M.-R. (Marjo-Riitta), Chen, Z. (Zhengming), Lawlor, D. A. (Debbie A.), Ala-Korpela, M. (Mika), Danesh, J. (John), Davey Smith, G. (George), Sattar, N. (Naveed), Butterworth, A. (Adam), Wuertz, P. (Peter), Sliz, E. (Eeva), Kettunen, J. (Johannes), Holmes, M. V. (Michael V.), Williams, C. O. (Clare Oliver), Boachie, C. (Charles), Wang, Q. (Qin), Maennikkoe, M. (Minna), Sebert, S. (Sylvain), Walters, R. (Robin), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Clarke, R. (Robert), Li, L. (Liming), Rankin, N. (Naomi), Welsh, P. (Paul), Delles, C. (Christian), Jukema, J. W. (J. Wouter), Trompet, S. (Stella), Ford, I. (Ian), Perola, M. (Markus), Salomaa, V. (Veikko), Jaervelin, M.-R. (Marjo-Riitta), Chen, Z. (Zhengming), Lawlor, D. A. (Debbie A.), Ala-Korpela, M. (Mika), Danesh, J. (John), Davey Smith, G. (George), Sattar, N. (Naveed), Butterworth, A. (Adam), and Wuertz, P. (Peter)
Abstract: Background: Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 population cohorts (N=72 185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R²=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P=2×10⁻⁷ for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detaile
Published: 2018

44. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Author: Ruuth, M. (Maija), Duy Nguyen, S. (Su), Vihervaara, T. (Terhi), Hilvo, M. (Mika), Laajala, T. D. (Teemu D), Kumar Kondadi, P. (Pradeep), Gisterå, A. (Anton), Lähteenmäki, H. (Hanna), Kittilä, T. (Tiia), Huusko, J. (Jenni), Uusitupa, M. (Matti), Schwab, U. (Ursula), Savolainen, M. J. (Markku J), Sinisalo, J. (Juha), Lokki, M.-L. (Marja-Liisa), Nieminen, M. S. (Markku S), Jula, A. (Antti), Perola, M. (Markus), Ylä-Herttula, S. (Seppo), Rudel, L. (Lawrence), Öörni, A. (Anssi), Baumann, M. (Marc), Baruch, A. (Amos), Laaksonen, R. (Reijo), Ketelhuth, D. F. (Daniel F J), Aittokallio, T. (Tero), Jauhiainen, M. (Matti), Käkelä, R. (Reijo), Borén, J. (Jan), Williams, K. J. (Kevin Jon), Kovanen, P. T. (Petri T), Öörni, K. (Katariina), Ruuth, M. (Maija), Duy Nguyen, S. (Su), Vihervaara, T. (Terhi), Hilvo, M. (Mika), Laajala, T. D. (Teemu D), Kumar Kondadi, P. (Pradeep), Gisterå, A. (Anton), Lähteenmäki, H. (Hanna), Kittilä, T. (Tiia), Huusko, J. (Jenni), Uusitupa, M. (Matti), Schwab, U. (Ursula), Savolainen, M. J. (Markku J), Sinisalo, J. (Juha), Lokki, M.-L. (Marja-Liisa), Nieminen, M. S. (Markku S), Jula, A. (Antti), Perola, M. (Markus), Ylä-Herttula, S. (Seppo), Rudel, L. (Lawrence), Öörni, A. (Anssi), Baumann, M. (Marc), Baruch, A. (Amos), Laaksonen, R. (Reijo), Ketelhuth, D. F. (Daniel F J), Aittokallio, T. (Tero), Jauhiainen, M. (Matti), Käkelä, R. (Reijo), Borén, J. (Jan), Williams, K. J. (Kevin Jon), Kovanen, P. T. (Petri T), and Öörni, K. (Katariina)
Abstract: Aims: Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization. Methods and results: We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.
Published: 2018

45. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

Author: Gregson, J.M. (John M.), Freitag, C.M. (Christine), Surendran, P. (Praveen), Stitziel, N.O. (Nathan), Chowdhury, R. (Rajiv), Burgess, S. (Stephen), Kaptoge, S. (Stephen), Gao, P. (Pei), Staley, J.R. (James R.), Willeit, J. (Johann), Nielsen, S.F. (Sune), Caslake, M. (Muriel), Trompet, S. (Stella), Polfus, L.M. (Linda M.), Kuulasmaa, K. (Kari), Kontto, J. (Jukka), Perola, M. (Markus), Blankenberg, S. (Stefan), Veronesi, G. (Giovanni), Gianfagna, F. (Francesco), Männistö, S. (Satu), Kimura, A. (Akinori), Lin, H. (Honghuang), Reilly, D.F. (Dermot F.), Gorski, M. (Mathias), Mijatovic, V. (Vladan), Munroe, P. (Patricia), Ehret, G.B. (Georg), Thompson, A. (Alex), Uria-Nickelsen, M. (Maria), Mälarstig, A. (Anders), Dehghan, A. (Abbas), Vogt, T.F. (Thomas F.), Sasaoka, T. (Taishi), Takeuchi, F. (Fumihiko), Kato, N. (Norihiro), Yamada, Y. (Yoshiji), Kee, F. (F.), Müller-Nurasyid, M. (Martina), Ferrieres, J. (Jean), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Salomaa, V. (Veikko), Boerwinkle, E.A. (Eric), Thompson, S.G. (Simon), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Packard, C.J. (Chris J.), Shafi Majumder, A.A. (Abdulla Al), Alam, D.S. (Dewan S.), Deloukas, P. (Panagiotis), Schunkert, H. (Heribert), Samani, N.J. (Nilesh), Kathiresan, S. (Sekar), Nordestgaard, B.G. (Børge), Saleheen, D. (Danish), Howson, J.M.M. (Joanna M.M.), Angelantonio, E. (Emanuele) di, Butterworth, A.S. (Adam), Danesh, J. (John), Gregson, J.M. (John M.), Freitag, C.M. (Christine), Surendran, P. (Praveen), Stitziel, N.O. (Nathan), Chowdhury, R. (Rajiv), Burgess, S. (Stephen), Kaptoge, S. (Stephen), Gao, P. (Pei), Staley, J.R. (James R.), Willeit, J. (Johann), Nielsen, S.F. (Sune), Caslake, M. (Muriel), Trompet, S. (Stella), Polfus, L.M. (Linda M.), Kuulasmaa, K. (Kari), Kontto, J. (Jukka), Perola, M. (Markus), Blankenberg, S. (Stefan), Veronesi, G. (Giovanni), Gianfagna, F. (Francesco), Männistö, S. (Satu), Kimura, A. (Akinori), Lin, H. (Honghuang), Reilly, D.F. (Dermot F.), Gorski, M. (Mathias), Mijatovic, V. (Vladan), Munroe, P. (Patricia), Ehret, G.B. (Georg), Thompson, A. (Alex), Uria-Nickelsen, M. (Maria), Mälarstig, A. (Anders), Dehghan, A. (Abbas), Vogt, T.F. (Thomas F.), Sasaoka, T. (Taishi), Takeuchi, F. (Fumihiko), Kato, N. (Norihiro), Yamada, Y. (Yoshiji), Kee, F. (F.), Müller-Nurasyid, M. (Martina), Ferrieres, J. (Jean), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Salomaa, V. (Veikko), Boerwinkle, E.A. (Eric), Thompson, S.G. (Simon), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Packard, C.J. (Chris J.), Shafi Majumder, A.A. (Abdulla Al), Alam, D.S. (Dewan S.), Deloukas, P. (Panagiotis), Schunkert, H. (Heribert), Samani, N.J. (Nilesh), Kathiresan, S. (Sekar), Nordestgaard, B.G. (Børge), Saleheen, D. (Danish), Howson, J.M.M. (Joanna M.M.), Angelantonio, E. (Emanuele) di, Butterworth, A.S. (Adam), and Danesh, J. (John)
Abstract: Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2 activity was decreased by 64% (p = 2.4 × 10-25) with carriage of any of the four loss-of-function variants, by 45% (p < 10-300) for every allele inherited at Val279Phe, and by 2.7% (p = 1.9 × 10-12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2 activity by 65% (p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a causal risk factor.
Published: 2017
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46. Rare and low-frequency coding variants alter human adult height

Author: Marouli, E. (Eirini), Graff, M.J. (Maud J.L.), Medina-Gomez, C. (Carolina), Lo, K.S., Wood, A.R. (Andrew), Kjaer, T.R. (Troels R.), Fine, R.S. (Rebecca S.), Lu, Y. (Yingchang), Schurmann, C. (Claudia), Highland, H. (Heather), Rüeger, S. (Sina), Thorleifsson, G. (Gudmar), Justice, A.E. (Anne), Lamparter, D. (David), Stirrups, K. (Kathy), Turcot, V. (Valérie), Young, K.L. (Kristin L.), Winkler, T.W. (Thomas W.), Esko, T. (Tõnu), Karaderi, T. (Tugce), Locke, A. (Adam), Masca, N.G.D. (Nicholas G.D.), Ng, M.C.Y. (Maggie C.Y.), Mudgal, P. (Poorva), Rivas, M.A. (Manuel), Vedantam, S. (Sailaja), Mahajan, A. (Anubha), Guo, X. (Xiuqing), Abecasis, G.R. (Gonçalo), Aben, K.K.H. (Katja), Adair, L.S. (Linda), Alam, D.S. (Dewan S.), Albrecht, E. (Eva), Allin, K.H. (Kristine H), Allison, M.A. (Matthew), Amouyel, P. (Philippe), Appel, E.V. (Emil V.), Arveiler, D. (Dominique), Asselbergs, F.W. (Folkert), Auer, P. (Paul), Balkau, B. (Beverley), Banas, B. (Bernhard), Bang, L.E. (Lia E.), Benn, M. (Marianne), Bergmann, S. (Sven), Bielak, L.F. (Lawrence F.), Blüher, M. (Matthias), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Böger, C.A. (Carsten), Bonnycastle, L.L. (Lori), Bork-Jensen, J. (Jette), Bots, M.L. (Michiel), Bottinger, E.P. (Erwin), Bowden, D.W. (Donald), Brandslund, I. (Ivan), Breen, G. (Gerome), Brilliant, M.H. (Murray H.), Broer, L. (Linda), Burt, A.D. (Alastair), Butterworth, A.S. (Adam), Carey, D.J. (David J.), Caulfield, M. (Mark), Chambers, J.C. (John), Chasman, D.I. (Daniel), Chen, Y.-D.I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Christensen, C. (Cramer), Chu, A.Y. (Audrey), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Cook, J.P. (James P.), Corley, J. (Janie), Galbany, J.C. (Jordi Corominas), Cox, A.J. (Amanda J.), Cuellar-Partida, G. (Gabriel), Danesh, J. (John), Davies, G. (Gail), Bakker, P.I.W. (Paul) de, Borst, G.J. (Gert) de, De Denus, S. (Simon), De Groot, M.C.H. (Mark C.H.), Mutsert, R. (Reneé) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Demerath, E.W. (Ellen), Hollander, A.I. (Anneke), Dennis, J. (Joe), Angelantonio, E. (Emanuele) di, Drenos, F. (Fotios), Du, M. (Mengmeng), Dunning, A.M. (Alison M.), Easton, D.F. (Douglas), Ebeling, T. (Tapani), Edwards, T.L. (Todd L.), Ellinor, P.T. (Patrick), Elliott, P. (Paul), Evangelou, E. (Evangelos), Farmaki, A.-E. (Aliki-Eleni), Faul, J.D. (Jessica D.), Feitosa, M.F. (Mary Furlan), Feng, S. (Shuang), Ferrannini, E. (Ele), Ferrario, M.M. (Marco M.), Ferrieres, J. (Jean), Florez, J.C. (Jose), Ford, I., Fornage, M. (Myriam), Franks, P.W. (Paul), Frikke-Schmidt, R. (Ruth), Galesloot, T.E. (Tessel), Gan, W. (Wei), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Giri, A. (Ayush), Girotto, S., Gordon, S.D. (Scott D.), Gordon-Larsen, P. (Penny), Gorski, M. (Mathias), Grarup, N. (Niels), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Gustafsson, S. (Stefan), Hansen, T. (T.), Harris, K.M. (Kathleen Mullan), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), He, L. (Liang), Heid, I.M. (Iris), Heikkilä, K. (Kauko), Helgeland, Ø. (Øyvind), Hernesniemi, J. (Jussi), Hewit, A.W. (Alex), Hocking, L.J. (Lynne), Hollensted, M. (Mette), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Howson, J.M.M. (Joanna M.M.), Hoyng, C.B. (Carel), Huang, P.L. (Paul L.), Hveem, K. (Kristian), Ikram, M.K. (Kamran), Ingelsson, E. (Erik), Jackson, A.U. (Anne), Jansson, J.-H. (Jan-Håkan), Jarvik, G.P. (Gail), Jensen, G.B. (Gorm B.), Jhun, M.A. (Min A.), Jia, Y. (Yucheng), Jiang, X. (Xuejuan), Johansson, S. (Stefan), Jørgensen, M.E. (Marit E.), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kahali, B. (Bratati), Kahn, R. (René), Kähönen, M. (Mika), Kamstrup, P.R. (Pia R.), Kanoni, S. (Stavroula), Kaprio, J. (Jaakko), Karaleftheri, M. (Maria), Kardia, S.L.R. (Sharon L.R.), Karpe, F. (Fredrik), Kee, F. (Frank), Keeman, J.N., Kiemeney, L.A.L.M. (Bart), Kitajima, H. (Hidetoshi), Kluivers, K.B. (Kirsten B.), Kocher, T., Komulainen, P. (Pirjo), Kontto, J. (Jukka), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Kovacs, P. (Peter), Kriebel, J. (Jennifer), Kuivaniemi, H. (Helena), Küry, S. (Sébastien), Kuusisto, J. (Johanna), La Bianca, M. (Martina), Laakso, M. (Markku), Lakka, T.A. (Timo), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Larson, E.B. (Eric B.), Lee, I.-T. (I-Te), Lehtimäki, T. (Terho), Lewis, C.E. (Cora E.), Li, H. (Huaixing), Li, J. (Jin), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Lin, L.-A. (Li-An), Lin, X. (Xu), Kao, W.H.L. (Wen), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y. (Yeheng), Liu, Y. (YongMei), Lophatananon, A. (Artitaya), Luan, J. (Jian'An), Lubitz, S.A. (Steven), Lyytikäinen, L.-P. (Leo-Pekka), Mackey, D.A. (David A.), Madden, P.A. (Pamela), Manning, A.K. (Alisa), Männistö, S. (Satu), Marenne, G. (Gaëlle), Marten, J. (Jonathan), Martin, N.G. (Nicholas), Mazul, A.L. (Angela L.), Meidtner, K. (Karina), Metspalu, A. (Andres), Mitchell, P. (Paul), Mohlke, K.L. (Karen), Mook-Kanamori, D.O. (Dennis), Morgan, A. (Anna), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Neville, M.J. (Matthew), Nielsen, S.F. (Sune), Nikus, K. (Kjell), Njolstad, P. (Pal), Nordestgaard, B.G. (Børge), Ntalla, I. (Ioanna), O'Connel, J.R. (Jeffrey R.), Oksa, H. (Heikki), Loohuis, L.M.O. (Loes M. Olde), Ophoff, R.A. (Roel), Owen, K.R. (Katharine R.), Packard, C.J. (Chris J.), Padmanabhan, S. (Sandosh), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Patel, A.P. (Aniruddh), Pattie, A. (Alison), Pedersen, O. (Oluf), Peissig, P.L. (Peggy L.), Peloso, G.M. (Gina), Pennell, C.E. (Craig), Perola, M. (Markus), Perry, J.A. (James A.), Perry, J.R.B. (John R.B.), Person, A.D. (Anthony), Pirie, A. (Ailith), Polasek, O. (Ozren), Posthuma, D. (Danielle), Raitakari, O.T. (Olli T.), Rasheed, A. (Asif), Rauramaa, R. (Rainer), Reilly, D.F. (Dermot F.), Reiner, A. (Alexander), Renström, F. (Frida), Ridker, P.M. (Paul), Rioux, J.D. (John), Robertson, N.R. (Neil), Robino, A. (Antonietta), Rolandsson, O. (Olov), Rudan, I. (Igor), Ruth, K.S. (Katherine S.), Saleheen, D. (Danish), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Sandow, K. (Kevin), Sapkota, Y. (Yadav), Sattar, N. (Naveed), Schmidt, M.K. (Marjanka), Schreiner, P.J. (Pamela), Schulze, M.B. (Matthias B), Scott, R.A. (Robert), Segura-Lepe, M.P. (Marcelo P.), Shah, S.H. (Svati), Sim, X. (Xueling), Sivapalaratnam, S. (Suthesh), Small, K.S. (Kerrin), Smith, A.V. (Albert Vernon), Smith, J.A. (Jennifer A), Southam, L. (Lorraine), Spector, T.D. (Timothy), Speliotes, E.K. (Elizabeth K.), Starr, J.M. (John), Steinthorsdottir, V. (Valgerdur), Stringham, H.M. (Heather), Stumvoll, M. (Michael), Surendran, P. (Praveen), Hart't, L.M. (Leen M.), Tansey, K.E. (Katherine E.), Tardif, J.-C. (Jean-Claude), Taylor, K.D. (Kent), Teumer, A. (Alexander), Thompson, D. (Deborah), Thorsteinsdottir, U. (Unnur), Thuesen, B.H. (Betina H.), Tönjes, A. (Anke), Tromp, G. (Gerard), Trompet, S. (Stella), Tsafantakis, E. (Emmanouil), Tuomilehto, J. (Jaakko), Tybjaerg-Hansen, A. (Anne), Tyrer, J.P. (Jonathan), Uher, R., Uitterlinden, A.G. (André), Ulivi, S. (Sheila), Van Der Laan, S.W. (Sander W.), Van Der Leij, A.R. (Andries R.), Duijn, C.M. (Cornelia) van, Schoor, N.M. (Natasja) van, Setten, J. (Jessica) van, Varbo, A. (Anette), Varga, T.V. (Tibor V.), Varma, R. (Rohit), Velez Edwards, D.R. (Digna R.), Vermeulen, S.H.H.M. (Sita), Vestergaard, H. (Henrik), Vitart, V. (Veronique), Vogt, T.F. (Thomas F.), Vozzi, D. (Diego), Walker, M. (Mark), Wang, F. (Feijie), Wang, C.A. (Carol A.), Wang, S. (Shuai), Wang, Y. (Yiqin), Wareham, N.J. (Nicholas J.), Warren, H. (Helen), Wessel, J. (Jennifer), Willems, S.M. (Sara), Wilson, J.F. (James), Witte, D.R. (Deniel), Woods, M.O. (Michael), Wu, Y. (Ying), Yaghootkar, H. (Hanieh), Yao, J. (Jiefen), Yao, P. (Pang), Yerges-Armstrong, L.M. (Laura), Young, R. (Robin), Zeggini, E. (Eleftheria), Zhan, X. (Xiaowei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zhao, W. (Wei), Zheng, H. (He), Zhou, W. (Wei), Rotter, J.I. (Jerome I.), Boehnke, M. (Michael), Kathiresan, S. (Sekar), McCarthy, M.I. (Mark I.), Willer, C.J. (Cristen), Zwart, J-A. (John-Anker), Borecki, I.B. (Ingrid), Liu, D. (Dajiang), North, K.E. (Kari), Heard-Costa, N.L. (Nancy), Pers, T.H. (Tune), Lindgren, C.M. (Cecilia M.), Oxvig, C. (Claus), Kutalik, Z. (Zoltán), Rivadeneira Ramirez, F. (Fernando), Loos, R.J.F. (Ruth), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Deloukas, P. (Panos), Lettre, G. (Guillaume), Marouli, E. (Eirini), Graff, M.J. (Maud J.L.), Medina-Gomez, C. (Carolina), Lo, K.S., Wood, A.R. (Andrew), Kjaer, T.R. (Troels R.), Fine, R.S. (Rebecca S.), Lu, Y. (Yingchang), Schurmann, C. (Claudia), Highland, H. (Heather), Rüeger, S. (Sina), Thorleifsson, G. (Gudmar), Justice, A.E. (Anne), Lamparter, D. (David), Stirrups, K. (Kathy), Turcot, V. (Valérie), Young, K.L. (Kristin L.), Winkler, T.W. (Thomas W.), Esko, T. (Tõnu), Karaderi, T. (Tugce), Locke, A. (Adam), Masca, N.G.D. (Nicholas G.D.), Ng, M.C.Y. (Maggie C.Y.), Mudgal, P. (Poorva), Rivas, M.A. (Manuel), Vedantam, S. (Sailaja), Mahajan, A. (Anubha), Guo, X. (Xiuqing), Abecasis, G.R. (Gonçalo), Aben, K.K.H. (Katja), Adair, L.S. (Linda), Alam, D.S. (Dewan S.), Albrecht, E. (Eva), Allin, K.H. (Kristine H), Allison, M.A. (Matthew), Amouyel, P. (Philippe), Appel, E.V. (Emil V.), Arveiler, D. (Dominique), Asselbergs, F.W. (Folkert), Auer, P. (Paul), Balkau, B. (Beverley), Banas, B. (Bernhard), Bang, L.E. (Lia E.), Benn, M. (Marianne), Bergmann, S. (Sven), Bielak, L.F. (Lawrence F.), Blüher, M. (Matthias), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Böger, C.A. (Carsten), Bonnycastle, L.L. (Lori), Bork-Jensen, J. (Jette), Bots, M.L. (Michiel), Bottinger, E.P. (Erwin), Bowden, D.W. (Donald), Brandslund, I. (Ivan), Breen, G. (Gerome), Brilliant, M.H. (Murray H.), Broer, L. (Linda), Burt, A.D. (Alastair), Butterworth, A.S. (Adam), Carey, D.J. (David J.), Caulfield, M. (Mark), Chambers, J.C. (John), Chasman, D.I. (Daniel), Chen, Y.-D.I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Christensen, C. (Cramer), Chu, A.Y. (Audrey), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Cook, J.P. (James P.), Corley, J. (Janie), Galbany, J.C. (Jordi Corominas), Cox, A.J. (Amanda J.), Cuellar-Partida, G. (Gabriel), Danesh, J. (John), Davies, G. (Gail), Bakker, P.I.W. (Paul) de, Borst, G.J. (Gert) de, De Denus, S. (Simon), De Groot, M.C.H. (Mark C.H.), Mutsert, R. (Reneé) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Demerath, E.W. (Ellen), Hollander, A.I. (Anneke), Dennis, J. (Joe), Angelantonio, E. (Emanuele) di, Drenos, F. (Fotios), Du, M. (Mengmeng), Dunning, A.M. (Alison M.), Easton, D.F. (Douglas), Ebeling, T. (Tapani), Edwards, T.L. (Todd L.), Ellinor, P.T. (Patrick), Elliott, P. (Paul), Evangelou, E. (Evangelos), Farmaki, A.-E. (Aliki-Eleni), Faul, J.D. (Jessica D.), Feitosa, M.F. (Mary Furlan), Feng, S. (Shuang), Ferrannini, E. (Ele), Ferrario, M.M. (Marco M.), Ferrieres, J. (Jean), Florez, J.C. (Jose), Ford, I., Fornage, M. (Myriam), Franks, P.W. (Paul), Frikke-Schmidt, R. (Ruth), Galesloot, T.E. (Tessel), Gan, W. (Wei), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Giri, A. (Ayush), Girotto, S., Gordon, S.D. (Scott D.), Gordon-Larsen, P. (Penny), Gorski, M. (Mathias), Grarup, N. (Niels), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Gustafsson, S. (Stefan), Hansen, T. (T.), Harris, K.M. (Kathleen Mullan), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), He, L. (Liang), Heid, I.M. (Iris), Heikkilä, K. (Kauko), Helgeland, Ø. (Øyvind), Hernesniemi, J. (Jussi), Hewit, A.W. (Alex), Hocking, L.J. (Lynne), Hollensted, M. (Mette), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Howson, J.M.M. (Joanna M.M.), Hoyng, C.B. (Carel), Huang, P.L. (Paul L.), Hveem, K. (Kristian), Ikram, M.K. (Kamran), Ingelsson, E. (Erik), Jackson, A.U. (Anne), Jansson, J.-H. (Jan-Håkan), Jarvik, G.P. (Gail), Jensen, G.B. (Gorm B.), Jhun, M.A. (Min A.), Jia, Y. (Yucheng), Jiang, X. (Xuejuan), Johansson, S. (Stefan), Jørgensen, M.E. (Marit E.), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kahali, B. (Bratati), Kahn, R. (René), Kähönen, M. (Mika), Kamstrup, P.R. (Pia R.), Kanoni, S. (Stavroula), Kaprio, J. (Jaakko), Karaleftheri, M. (Maria), Kardia, S.L.R. (Sharon L.R.), Karpe, F. (Fredrik), Kee, F. (Frank), Keeman, J.N., Kiemeney, L.A.L.M. (Bart), Kitajima, H. (Hidetoshi), Kluivers, K.B. (Kirsten B.), Kocher, T., Komulainen, P. (Pirjo), Kontto, J. (Jukka), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Kovacs, P. (Peter), Kriebel, J. (Jennifer), Kuivaniemi, H. (Helena), Küry, S. (Sébastien), Kuusisto, J. (Johanna), La Bianca, M. (Martina), Laakso, M. (Markku), Lakka, T.A. (Timo), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Larson, E.B. (Eric B.), Lee, I.-T. (I-Te), Lehtimäki, T. (Terho), Lewis, C.E. (Cora E.), Li, H. (Huaixing), Li, J. (Jin), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Lin, L.-A. (Li-An), Lin, X. (Xu), Kao, W.H.L. (Wen), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y. (Yeheng), Liu, Y. (YongMei), Lophatananon, A. (Artitaya), Luan, J. (Jian'An), Lubitz, S.A. (Steven), Lyytikäinen, L.-P. (Leo-Pekka), Mackey, D.A. (David A.), Madden, P.A. (Pamela), Manning, A.K. (Alisa), Männistö, S. (Satu), Marenne, G. (Gaëlle), Marten, J. (Jonathan), Martin, N.G. (Nicholas), Mazul, A.L. (Angela L.), Meidtner, K. (Karina), Metspalu, A. (Andres), Mitchell, P. (Paul), Mohlke, K.L. (Karen), Mook-Kanamori, D.O. (Dennis), Morgan, A. (Anna), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Neville, M.J. (Matthew), Nielsen, S.F. (Sune), Nikus, K. (Kjell), Njolstad, P. (Pal), Nordestgaard, B.G. (Børge), Ntalla, I. (Ioanna), O'Connel, J.R. (Jeffrey R.), Oksa, H. (Heikki), Loohuis, L.M.O. (Loes M. Olde), Ophoff, R.A. (Roel), Owen, K.R. (Katharine R.), Packard, C.J. (Chris J.), Padmanabhan, S. (Sandosh), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Patel, A.P. (Aniruddh), Pattie, A. (Alison), Pedersen, O. (Oluf), Peissig, P.L. (Peggy L.), Peloso, G.M. (Gina), Pennell, C.E. (Craig), Perola, M. (Markus), Perry, J.A. (James A.), Perry, J.R.B. (John R.B.), Person, A.D. (Anthony), Pirie, A. (Ailith), Polasek, O. (Ozren), Posthuma, D. (Danielle), Raitakari, O.T. (Olli T.), Rasheed, A. (Asif), Rauramaa, R. (Rainer), Reilly, D.F. (Dermot F.), Reiner, A. (Alexander), Renström, F. (Frida), Ridker, P.M. (Paul), Rioux, J.D. (John), Robertson, N.R. (Neil), Robino, A. (Antonietta), Rolandsson, O. (Olov), Rudan, I. (Igor), Ruth, K.S. (Katherine S.), Saleheen, D. (Danish), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Sandow, K. (Kevin), Sapkota, Y. (Yadav), Sattar, N. (Naveed), Schmidt, M.K. (Marjanka), Schreiner, P.J. (Pamela), Schulze, M.B. (Matthias B), Scott, R.A. (Robert), Segura-Lepe, M.P. (Marcelo P.), Shah, S.H. (Svati), Sim, X. (Xueling), Sivapalaratnam, S. (Suthesh), Small, K.S. (Kerrin), Smith, A.V. (Albert Vernon), Smith, J.A. (Jennifer A), Southam, L. (Lorraine), Spector, T.D. (Timothy), Speliotes, E.K. (Elizabeth K.), Starr, J.M. (John), Steinthorsdottir, V. (Valgerdur), Stringham, H.M. (Heather), Stumvoll, M. (Michael), Surendran, P. (Praveen), Hart't, L.M. (Leen M.), Tansey, K.E. (Katherine E.), Tardif, J.-C. (Jean-Claude), Taylor, K.D. (Kent), Teumer, A. (Alexander), Thompson, D. (Deborah), Thorsteinsdottir, U. (Unnur), Thuesen, B.H. (Betina H.), Tönjes, A. (Anke), Tromp, G. (Gerard), Trompet, S. (Stella), Tsafantakis, E. (Emmanouil), Tuomilehto, J. (Jaakko), Tybjaerg-Hansen, A. (Anne), Tyrer, J.P. (Jonathan), Uher, R., Uitterlinden, A.G. (André), Ulivi, S. (Sheila), Van Der Laan, S.W. (Sander W.), Van Der Leij, A.R. (Andries R.), Duijn, C.M. (Cornelia) van, Schoor, N.M. (Natasja) van, Setten, J. (Jessica) van, Varbo, A. (Anette), Varga, T.V. (Tibor V.), Varma, R. (Rohit), Velez Edwards, D.R. (Digna R.), Vermeulen, S.H.H.M. (Sita), Vestergaard, H. (Henrik), Vitart, V. (Veronique), Vogt, T.F. (Thomas F.), Vozzi, D. (Diego), Walker, M. (Mark), Wang, F. (Feijie), Wang, C.A. (Carol A.), Wang, S. (Shuai), Wang, Y. (Yiqin), Wareham, N.J. (Nicholas J.), Warren, H. (Helen), Wessel, J. (Jennifer), Willems, S.M. (Sara), Wilson, J.F. (James), Witte, D.R. (Deniel), Woods, M.O. (Michael), Wu, Y. (Ying), Yaghootkar, H. (Hanieh), Yao, J. (Jiefen), Yao, P. (Pang), Yerges-Armstrong, L.M. (Laura), Young, R. (Robin), Zeggini, E. (Eleftheria), Zhan, X. (Xiaowei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zhao, W. (Wei), Zheng, H. (He), Zhou, W. (Wei), Rotter, J.I. (Jerome I.), Boehnke, M. (Michael), Kathiresan, S. (Sekar), McCarthy, M.I. (Mark I.), Willer, C.J. (Cristen), Zwart, J-A. (John-Anker), Borecki, I.B. (Ingrid), Liu, D. (Dajiang), North, K.E. (Kari), Heard-Costa, N.L. (Nancy), Pers, T.H. (Tune), Lindgren, C.M. (Cecilia M.), Oxvig, C. (Claus), Kutalik, Z. (Zoltán), Rivadeneira Ramirez, F. (Fernando), Loos, R.J.F. (Ruth), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Deloukas, P. (Panos), and Lettre, G. (Guillaume)
Abstract: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of I
Published: 2017
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47. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Author: Mace, A. (Aurelien), Tuke, M.A. (Marcus A.), Deelen, P. (Patrick), Kristiansson, K. (Kati), Mattsson, H. (Hannele), Nõukas, M. (Margit), Sapkota, Y. (Yadav), Schick, U.M. (Ursula), Porcu, E. (Eleonora), Rüeger, S. (Sina), McDaid, A.F. (Aaron F.), Porteous, D.J. (David J.), Winkler, T.W. (Thomas W.), Salvi, E. (Erika), Shrine, N.R.G. (Nick), Liu, X. (Xueping), Ang, W.Q. (Wei), Zhang, W. (Weihua), Feitosa, M.F., Venturini, C. (Cristina), Most, P.J. (Peter) van der, Rosengren, A. (Anders), Wood, A.R. (Andrew), Beaumont, R.N. (Robin N.), Jones, S.E. (Samuel E.), Ruth, K.S. (Katherine S.), Yaghootkar, H. (Hanieh), Tyrrell, A.W.R., Havulinna, A.S. (Aki), Boers, H. (Harmen), Mägi, R. (Reedik), Kriebel, J. (Jennifer), Müller-Nurasyid, M. (Martina), Perola, M. (Markus), Nieminen, M.S. (Markku), Lokki, M.L., Kähönen, M. (Mika), Viikari, J. (Jorma), Geller, F. (Frank), Lahti, J., Palotie, A. (Aarno), Koponen, P. (Päivikki), Lundqvist, A. (Annamari), Rissanen, H. (Harri), Bottinger, E.P. (Erwin), Afaq, S. (Saima), Wojczynski, M.K. (Mary ), Lenzini, P. (Petra), Nolte, I.M. (Ilja), Sparsø, T. (Thomas), Schupf, N. (Nicole), Christensen, K. (Kaare), Perls, T.T. (Thomas T.), Newman, A.B. (Anne B.), Werge, T.M. (Thomas), Snieder, H. (Harold), Spector, T.D. (Timothy), Chambers, J.C. (John C.), Koskinen, S. (Seppo), Melbye, M. (Mads), Raitakari, O.T. (Olli T.), Lehtimäki, T. (Terho), Tobin, M.D. (Martin), Wain, L.V. (Louise V.), Sinisalo, J. (Juha), Peters, A. (Annette), Meitinger, T. (Thomas), Martin, N.G. (Nicholas), Wray, N.R. (Naomi), Montgomery, G.W. (Grant W.), Medland, S.E. (Sarah), Swertz, M.A. (Morris A.), Vartiainen, E. (Erkki), Borodulin, K. (Katja), Männistö, S. (Satu), Murray, A. (Anna), Bochud, M. (Murielle), Jacquemont, S. (Sébastien), Rivadeneira, F. (Fernando), Hansen, T. (Thomas), Oldehinkel, A.J. (Albertine), Mangino, M. (Massimo), Province, M.A. (Mike), Deloukas, P. (Panos), Kooner, J.S. (Jaspal S.), Freathy, R.M. (Rachel), Pennell, C.E. (Craig), Feenstra, B. (Bjarke), Strachan, D.P. (David), Lettre, G. (Guillaume), Hirschhorn, J.N. (Joel), Cusi, D. (Daniele), Heid, I.M. (Iris), Hayward, C. (Caroline), Männik, K. (Katrin), Beckmann, J.S. (Jacques), Loos, R.J.F. (Ruth), Nyholt, D.R. (Dale), Metspalu, A. (Andres), Hagen, K. (Knut), Weedon, M.N. (Michael), Salomaa, V. (Veikko), Franke, L. (Lude), Reymond, A. (Alexandre), Frayling, T.M. (Timothy M.), Kutalik, Z. (Zoltán), Mace, A. (Aurelien), Tuke, M.A. (Marcus A.), Deelen, P. (Patrick), Kristiansson, K. (Kati), Mattsson, H. (Hannele), Nõukas, M. (Margit), Sapkota, Y. (Yadav), Schick, U.M. (Ursula), Porcu, E. (Eleonora), Rüeger, S. (Sina), McDaid, A.F. (Aaron F.), Porteous, D.J. (David J.), Winkler, T.W. (Thomas W.), Salvi, E. (Erika), Shrine, N.R.G. (Nick), Liu, X. (Xueping), Ang, W.Q. (Wei), Zhang, W. (Weihua), Feitosa, M.F., Venturini, C. (Cristina), Most, P.J. (Peter) van der, Rosengren, A. (Anders), Wood, A.R. (Andrew), Beaumont, R.N. (Robin N.), Jones, S.E. (Samuel E.), Ruth, K.S. (Katherine S.), Yaghootkar, H. (Hanieh), Tyrrell, A.W.R., Havulinna, A.S. (Aki), Boers, H. (Harmen), Mägi, R. (Reedik), Kriebel, J. (Jennifer), Müller-Nurasyid, M. (Martina), Perola, M. (Markus), Nieminen, M.S. (Markku), Lokki, M.L., Kähönen, M. (Mika), Viikari, J. (Jorma), Geller, F. (Frank), Lahti, J., Palotie, A. (Aarno), Koponen, P. (Päivikki), Lundqvist, A. (Annamari), Rissanen, H. (Harri), Bottinger, E.P. (Erwin), Afaq, S. (Saima), Wojczynski, M.K. (Mary ), Lenzini, P. (Petra), Nolte, I.M. (Ilja), Sparsø, T. (Thomas), Schupf, N. (Nicole), Christensen, K. (Kaare), Perls, T.T. (Thomas T.), Newman, A.B. (Anne B.), Werge, T.M. (Thomas), Snieder, H. (Harold), Spector, T.D. (Timothy), Chambers, J.C. (John C.), Koskinen, S. (Seppo), Melbye, M. (Mads), Raitakari, O.T. (Olli T.), Lehtimäki, T. (Terho), Tobin, M.D. (Martin), Wain, L.V. (Louise V.), Sinisalo, J. (Juha), Peters, A. (Annette), Meitinger, T. (Thomas), Martin, N.G. (Nicholas), Wray, N.R. (Naomi), Montgomery, G.W. (Grant W.), Medland, S.E. (Sarah), Swertz, M.A. (Morris A.), Vartiainen, E. (Erkki), Borodulin, K. (Katja), Männistö, S. (Satu), Murray, A. (Anna), Bochud, M. (Murielle), Jacquemont, S. (Sébastien), Rivadeneira, F. (Fernando), Hansen, T. (Thomas), Oldehinkel, A.J. (Albertine), Mangino, M. (Massimo), Province, M.A. (Mike), Deloukas, P. (Panos), Kooner, J.S. (Jaspal S.), Freathy, R.M. (Rachel), Pennell, C.E. (Craig), Feenstra, B. (Bjarke), Strachan, D.P. (David), Lettre, G. (Guillaume), Hirschhorn, J.N. (Joel), Cusi, D. (Daniele), Heid, I.M. (Iris), Hayward, C. (Caroline), Männik, K. (Katrin), Beckmann, J.S. (Jacques), Loos, R.J.F. (Ruth), Nyholt, D.R. (Dale), Metspalu, A. (Andres), Hagen, K. (Knut), Weedon, M.N. (Michael), Salomaa, V. (Veikko), Franke, L. (Lude), Reymond, A. (Alexandre), Frayling, T.M. (Timothy M.), and Kutalik, Z. (Zoltán)
Abstract: There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increa
Published: 2017
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48. Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts

Author: Mozaffarian, D. (Dariush), Dashti, H.S. (Hassan S.), Wojczynski, M.K. (Mary ), Chu, A.Y. (Audrey), Nettleton, J.A. (Jennifer ), Männistö, S. (Satu), Kristiansson, K. (Kati), Reedik, M. (Mägi), Lahti, J. (Jari), Houston, D.K. (Denise), Cornelis, M. (Marilyn), Rooij, F.J.A. (Frank) van, Dimitriou, M. (Maria), Kanoni, S. (Stavroula), Mikkilä, V. (Vera), Steffen, L.M. (Lyn M.), De Oliveira Otto, M.C. (Marcia C), Qi, L. (Lu), Psaty, B.M. (Bruce), Djoussé, L. (Luc), Rotter, J.I. (Jerome I.), Harald, K. (Kennet), Perola, M. (Markus), Rissanen, H. (Harri), Jula, A. (Antti), Krista, F. (Fischer), Mihailov, E. (Evelin), Feitosa, M.F. (Mary Furlan), Ngwa, J.S., Xue, L. (Luting), Jacques, P.F. (Paul F.), Perälä, M.-M., Palotie, A. (Aarno), Liu, Y. (YongMei), Nalls, N.A. (Nike A.), Ferrucci, L. (Luigi), Hernandez, D.G. (Dena), Manichaikul, A. (Ani), Tsai, M.Y. (Michael), Kiefte-de Jong, J.C. (Jessica), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rallidis, L.S. (Loukianos), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Buring, J.E. (Julie), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Viikari, J. (Jorma), Lemaitre, R.N. (Rozenn ), Salomaa, V. (Veikko), Knekt, P., Metspalu, A. (Andres), Borecki, I.B. (Ingrid), Cupples, L.A. (Adrienne), Hagen, K. (Knut), Kritchevsky, S.B. (Stephen), Bandinelli, S. (Stefania), Siscovick, D.S. (David), Franco, O.H. (Oscar), Deloukas, P. (Panos), Dedoussis, G.V. (George), Chasman, D.I. (Daniel), Raitakari, O. (Olli), Tanaka, T. (Toshiko), Mozaffarian, D. (Dariush), Dashti, H.S. (Hassan S.), Wojczynski, M.K. (Mary ), Chu, A.Y. (Audrey), Nettleton, J.A. (Jennifer ), Männistö, S. (Satu), Kristiansson, K. (Kati), Reedik, M. (Mägi), Lahti, J. (Jari), Houston, D.K. (Denise), Cornelis, M. (Marilyn), Rooij, F.J.A. (Frank) van, Dimitriou, M. (Maria), Kanoni, S. (Stavroula), Mikkilä, V. (Vera), Steffen, L.M. (Lyn M.), De Oliveira Otto, M.C. (Marcia C), Qi, L. (Lu), Psaty, B.M. (Bruce), Djoussé, L. (Luc), Rotter, J.I. (Jerome I.), Harald, K. (Kennet), Perola, M. (Markus), Rissanen, H. (Harri), Jula, A. (Antti), Krista, F. (Fischer), Mihailov, E. (Evelin), Feitosa, M.F. (Mary Furlan), Ngwa, J.S., Xue, L. (Luting), Jacques, P.F. (Paul F.), Perälä, M.-M., Palotie, A. (Aarno), Liu, Y. (YongMei), Nalls, N.A. (Nike A.), Ferrucci, L. (Luigi), Hernandez, D.G. (Dena), Manichaikul, A. (Ani), Tsai, M.Y. (Michael), Kiefte-de Jong, J.C. (Jessica), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rallidis, L.S. (Loukianos), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Buring, J.E. (Julie), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Viikari, J. (Jorma), Lemaitre, R.N. (Rozenn ), Salomaa, V. (Veikko), Knekt, P., Metspalu, A. (Andres), Borecki, I.B. (Ingrid), Cupples, L.A. (Adrienne), Hagen, K. (Knut), Kritchevsky, S.B. (Stephen), Bandinelli, S. (Stefania), Siscovick, D.S. (David), Franco, O.H. (Oscar), Deloukas, P. (Panos), Dedoussis, G.V. (George), Chasman, D.I. (Daniel), Raitakari, O. (Olli), and Tanaka, T. (Toshiko)
Abstract: Background: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. Objective: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. Design: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86, 467) and EPA +DHA (n = 62, 265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. Results: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13
Published: 2017
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49. Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

Author: Graff, M.J. (Maud J.L.), Scott, R.A. (Robert), Justice, A.E. (Anne), Young, K.L. (Kristin L.), Feitosa, M.F. (Mary Furlan), Barata, L. (Llilda), Winkler, T.W. (Thomas W.), Chu, A.Y. (Audrey), Mahajan, A. (Anubha), Hadley, D. (David), Xue, L. (Luting), Workalemahu, T. (Tsegaselassie), Heard-Costa, N.L. (Nancy), Hoed, M. (Marcel) den, Ahluwalia, T.S. (Tarunveer Singh), Qi, Q., Ngwa, J.S., Renström, F. (Frida), Quaye, L. (Lydia), Eicher, J.D. (John D.), Hayes, J.E. (James E.), Cornelis, M. (Marilyn), Kutalik, Z. (Zoltán), Lim, E. (Elise), Luan, J. (Jian'An), Huffman, J.E. (Jennifer), Zhang, W. (Weihua), Zhao, W. (Wei), Griffin, P.J. (Paula J.), Haller, T. (Toomas), Ahmad, S. (Shafqat), Marques-Vidal, P. (Pedro), Bien, S. (Stephanie), Yengo, L. (Loic), Teumer, A. (Alexander), Smith, A.V. (Albert Vernon), Kumari, M. (Meena), Harder, M.N. (Marie Neergaard), Justesen, J.M. (Johanne M.), Kleber, M.E. (Marcus), Hollensted, M. (Mette), Lohman, K. (Kurt), Rivera, N.V. (Natalia), Whitfield, J.B. (John B.), Zhao, J.H. (Jing Hua), Stringham, H.M. (Heather), Lyytikäinen, L.-P. (Leo-Pekka), Huppertz, C. (Charlotte), Willemsen, G.A.H.M. (Gonneke), Peyrot, W.J. (Wouter ), Wu, Y. (Ying), Kristiansson, K. (Kati), Demirkan, A. (Ayşe), Fornage, M. (Myriam), Hassinen, M. (Maija), Bielak, L.F. (Lawrence F.), Cadby, G. (Gemma), Tanaka, T. (Toshiko), Mägi, R. (Reedik), Most, P.J. (Peter) van der, Jackson, A.U. (Anne), Bragg-Gresham, J.L. (Jennifer L.), Vitart, V. (Veronique), Marten, J. (Jonathan), Navarro, P. (Pau), Bellis, C. (Claire), Pasko, D. (Dorota), Johansson, Å. (Åsa), Snitker, S. (Soren), Cheng, Y.-C. (Yu-Ching), Eriksson, J. (Joel), Lim, U. (Unhee), Aadahl, M. (Mette), Adair, L.S. (Linda), Amin, N. (Najaf), Balkau, B. (Beverley), Auvinen, J. (Juha), Beilby, J.P. (John), Bergman, R.N. (Richard N.), Bergmann, S.M. (Sven), Bertoni, A.G. (Alain G.), Blangero, J. (John), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borja, J.B. (Judith), Brage, S. (Soren), Busonero, F., Buyske, S. (Steven), Campbell, H. (Harry), Chines, P.S. (Peter), Collins, F.S. (Francis), Corre, T. (Tanguy), Smith, G.D. (George Davey), Delgado, G., Dueker, N. (Nicole), Dörr, M. (Marcus), Ebeling, T. (Tapani), Eiriksdottir, G. (Gudny), Esko, T. (Tõnu), Faul, J.D. (Jessica D.), Fu, M. (Mao), Færch, K. (Kristine), Gieger, C. (Christian), Gläser, S., Gong, J. (Jian), Gordon-Larsen, P. (Penny), Grallert, H. (Harald), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grootheest, G. (Gerard) van, Harald, K. (Kennet), Hastie, N. (Nick), Havulinna, A.S. (Aki), Hernandez, D.G. (Dena), Hindorff, L.A. (Lucia A), Hocking, L.J. (Lynne), Holmens, O.L. (Oddgeir L.), Holzapfel, C. (Christina), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Huang, T. (Tao), Hui, J. (Jennie), Huth, C. (Cornelia), Hutri-Kähönen, N. (Nina), James, A. (Alan), Jansson, J.-O. (John-Olov), Jhun, M.A. (Min A.), Juonala, M. (Markus), Kinnunen, L. (Leena), Koistinen, H. (Heikki), Kolcic, I. (Ivana), Komulainen, P. (Pirjo), Kuusisto, J. (Johanna), Kvaløy, K. (Kirsti), Kähönen, M. (Mika), Lakka, T.A. (Timo), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lindgren, C.M. (Cecilia M.), Lorentzon, M. (Mattias), Luben, R.N. (Robert), Marre, M. (Michel), Milaneschi, Y. (Yuri), Monda, K.L. (Keri), Montgomery, G.W. (Grant W.), Moor, M.H.M. de, Mulas, A. (Antonella), Müller-Nurasyid, M. (Martina), Musk, A.W., Männikkö, R. (Reija), Männistö, S. (Satu), Narisu, N. (Narisu), Nauck, M. (Matthias), Nettleton, J.A. (Jennifer ), Nolte, I.M. (Ilja M.), Oldehinkel, A.J. (Albertine), Olden, M. (Matthias), Ong, K.K. (Ken K.), Padmanabhan, S. (Sandosh), Paternoster, L. (Lavinia), Perez, J. (Jeremiah), Perola, M. (Markus), Peters, A. (Annette), Peters, U. (Ulrike), Peyser, P.A. (Patricia A.), Prokopenko, I. (Inga), Puolijoki, H. (Hannu), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rasmussen-Torvik, L.J. (Laura J.), Rawal, R. (Rajesh), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Rudan, I. (Igor), Sarti, C. (Cinzia), Sarzynski, M.A. (Mark A.), Savonen, K. (Kai), Scott, W.R. (William R.), Sanna, S. (Serena), Shuldiner, A.R. (Alan), Sidney, S. (Steve), Silbernagel, G. (Günther), Smith, B.H., Smith, J.A. (Jennifer A), Snieder, H. (Harold), Stancáková, A. (Alena), Sternfeld, B. (Barbara), Swift, A.J. (Amy), Tammelin, T. (Tuija), Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Vandenput, L. (Liesbeth), Vestergaard, H. (Henrik), Vliet-Ostaptchouk, J.V. (Jana) van, Vohl, M.-C. (Marie-Claude), Völker, U. (Uwe), Waeber, G. (Gérard), Walker, M. (Mark), Wild, S. (Sarah), Wong, A. (Andrew), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Zubair, N. (Niha), Haiman, C.A. (Christopher), LeMarchand, L. (Loic), Gyllensten, U. (Ulf), Ohlsson, C. (Claes), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Perusse, L. (Louis), Wilson, J.F. (James), Hayward, C. (Caroline), Polasek, O. (Ozren), Cucca, F. (Francesco), Hveem, K. (Kristian), Hartman, C.A. (Catharina A.), Tönjes, A. (Anke), Bandinelli, S. (Stefania), Palmer, L.J. (Lyle J.), Kardia, S.L.R. (Sharon L. R.), Rauramaa, R. (Rainer), Sørensen, T.I.A. (Thorkild), Tuomilehto, J. (Jaakko), Salomaa, V. (Veikko), Penninx, B.W.J.H. (Brenda), Geus, E.J.C. (Eco) de, Boomsma, D.I. (Dorret), Lehtimäki, T. (Terho), Mangino, M. (Massimo), Laakso, M. (Markku), Bouchard, C. (Claude), Martin, N.G. (Nicholas), Kuh, D. (Diana), Liu, Y. (YongMei), Linneberg, A. (Allan), März, W. (Winfried), Strauch, K. (Konstantin), Kivimaki, M. (Mika), Harris, T.B. (Tamara), Gudnason, V. (Vilmundur), Völzke, H. (Henry), Qi, L. (Lu), Jarvelin, M.-R. (Marjo-Riitta), Chambers, J.C. (John), Kooner, J.S. (Jaspal S.), Froguel, P. (Philippe), Kooperberg, C. (Charles), Vollenweider, P. (Peter), Hallmans, G. (Göran), Hansen, T. (T.), Pedersen, O. (Oluf), Metspalu, A. (Andres), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Weir, D.R. (David), Porteous, D.J. (David J.), Boerwinkle, E.A. (Eric), Chasman, D.I. (Daniel), Abecasis, G.R. (Gonçalo R.), Barroso, I.E. (Inês), McCarthy, M.I. (Mark I.), Frayling, T.M. (Timothy), O’Connell, J.R. (Jeffrey R.), Duijn, C.M. (Cornelia) van, Boehnke, M. (Michael), Heid, I.M. (Iris), Mohlke, K.L. (Karen), Strachan, D.P. (David), Fox, C.S. (Caroline), Liu, C.-T. (Ching-Ti), Hirschhorn, J.N. (Joel), Klein, R.J. (Robert J.), Johnson, A.D. (Andrew), Borecki, I.B. (Ingrid), Franks, P.W. (Paul), North, K.E. (Kari), Cupples, L.A. (Adrienne), Loos, R.J.F. (Ruth), Kilpeläinen, T.O. (Tuomas), Graff, M.J. (Maud J.L.), Scott, R.A. (Robert), Justice, A.E. (Anne), Young, K.L. (Kristin L.), Feitosa, M.F. (Mary Furlan), Barata, L. (Llilda), Winkler, T.W. (Thomas W.), Chu, A.Y. (Audrey), Mahajan, A. (Anubha), Hadley, D. (David), Xue, L. (Luting), Workalemahu, T. (Tsegaselassie), Heard-Costa, N.L. (Nancy), Hoed, M. (Marcel) den, Ahluwalia, T.S. (Tarunveer Singh), Qi, Q., Ngwa, J.S., Renström, F. (Frida), Quaye, L. (Lydia), Eicher, J.D. (John D.), Hayes, J.E. (James E.), Cornelis, M. (Marilyn), Kutalik, Z. (Zoltán), Lim, E. (Elise), Luan, J. (Jian'An), Huffman, J.E. (Jennifer), Zhang, W. (Weihua), Zhao, W. (Wei), Griffin, P.J. (Paula J.), Haller, T. (Toomas), Ahmad, S. (Shafqat), Marques-Vidal, P. (Pedro), Bien, S. (Stephanie), Yengo, L. (Loic), Teumer, A. (Alexander), Smith, A.V. (Albert Vernon), Kumari, M. (Meena), Harder, M.N. (Marie Neergaard), Justesen, J.M. (Johanne M.), Kleber, M.E. (Marcus), Hollensted, M. (Mette), Lohman, K. (Kurt), Rivera, N.V. (Natalia), Whitfield, J.B. (John B.), Zhao, J.H. (Jing Hua), Stringham, H.M. (Heather), Lyytikäinen, L.-P. (Leo-Pekka), Huppertz, C. (Charlotte), Willemsen, G.A.H.M. (Gonneke), Peyrot, W.J. (Wouter ), Wu, Y. (Ying), Kristiansson, K. (Kati), Demirkan, A. (Ayşe), Fornage, M. (Myriam), Hassinen, M. (Maija), Bielak, L.F. (Lawrence F.), Cadby, G. (Gemma), Tanaka, T. (Toshiko), Mägi, R. (Reedik), Most, P.J. (Peter) van der, Jackson, A.U. (Anne), Bragg-Gresham, J.L. (Jennifer L.), Vitart, V. (Veronique), Marten, J. (Jonathan), Navarro, P. (Pau), Bellis, C. (Claire), Pasko, D. (Dorota), Johansson, Å. (Åsa), Snitker, S. (Soren), Cheng, Y.-C. (Yu-Ching), Eriksson, J. (Joel), Lim, U. (Unhee), Aadahl, M. (Mette), Adair, L.S. (Linda), Amin, N. (Najaf), Balkau, B. (Beverley), Auvinen, J. (Juha), Beilby, J.P. (John), Bergman, R.N. (Richard N.), Bergmann, S.M. (Sven), Bertoni, A.G. (Alain G.), Blangero, J. (John), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borja, J.B. (Judith), Brage, S. (Soren), Busonero, F., Buyske, S. (Steven), Campbell, H. (Harry), Chines, P.S. (Peter), Collins, F.S. (Francis), Corre, T. (Tanguy), Smith, G.D. (George Davey), Delgado, G., Dueker, N. (Nicole), Dörr, M. (Marcus), Ebeling, T. (Tapani), Eiriksdottir, G. (Gudny), Esko, T. (Tõnu), Faul, J.D. (Jessica D.), Fu, M. (Mao), Færch, K. (Kristine), Gieger, C. (Christian), Gläser, S., Gong, J. (Jian), Gordon-Larsen, P. (Penny), Grallert, H. (Harald), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grootheest, G. (Gerard) van, Harald, K. (Kennet), Hastie, N. (Nick), Havulinna, A.S. (Aki), Hernandez, D.G. (Dena), Hindorff, L.A. (Lucia A), Hocking, L.J. (Lynne), Holmens, O.L. (Oddgeir L.), Holzapfel, C. (Christina), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Huang, T. (Tao), Hui, J. (Jennie), Huth, C. (Cornelia), Hutri-Kähönen, N. (Nina), James, A. (Alan), Jansson, J.-O. (John-Olov), Jhun, M.A. (Min A.), Juonala, M. (Markus), Kinnunen, L. (Leena), Koistinen, H. (Heikki), Kolcic, I. (Ivana), Komulainen, P. (Pirjo), Kuusisto, J. (Johanna), Kvaløy, K. (Kirsti), Kähönen, M. (Mika), Lakka, T.A. (Timo), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lindgren, C.M. (Cecilia M.), Lorentzon, M. (Mattias), Luben, R.N. (Robert), Marre, M. (Michel), Milaneschi, Y. (Yuri), Monda, K.L. (Keri), Montgomery, G.W. (Grant W.), Moor, M.H.M. de, Mulas, A. (Antonella), Müller-Nurasyid, M. (Martina), Musk, A.W., Männikkö, R. (Reija), Männistö, S. (Satu), Narisu, N. (Narisu), Nauck, M. (Matthias), Nettleton, J.A. (Jennifer ), Nolte, I.M. (Ilja M.), Oldehinkel, A.J. (Albertine), Olden, M. (Matthias), Ong, K.K. (Ken K.), Padmanabhan, S. (Sandosh), Paternoster, L. (Lavinia), Perez, J. (Jeremiah), Perola, M. (Markus), Peters, A. (Annette), Peters, U. (Ulrike), Peyser, P.A. (Patricia A.), Prokopenko, I. (Inga), Puolijoki, H. (Hannu), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rasmussen-Torvik, L.J. (Laura J.), Rawal, R. (Rajesh), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Rudan, I. (Igor), Sarti, C. (Cinzia), Sarzynski, M.A. (Mark A.), Savonen, K. (Kai), Scott, W.R. (William R.), Sanna, S. (Serena), Shuldiner, A.R. (Alan), Sidney, S. (Steve), Silbernagel, G. (Günther), Smith, B.H., Smith, J.A. (Jennifer A), Snieder, H. (Harold), Stancáková, A. (Alena), Sternfeld, B. (Barbara), Swift, A.J. (Amy), Tammelin, T. (Tuija), Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Vandenput, L. (Liesbeth), Vestergaard, H. (Henrik), Vliet-Ostaptchouk, J.V. (Jana) van, Vohl, M.-C. (Marie-Claude), Völker, U. (Uwe), Waeber, G. (Gérard), Walker, M. (Mark), Wild, S. (Sarah), Wong, A. (Andrew), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Zubair, N. (Niha), Haiman, C.A. (Christopher), LeMarchand, L. (Loic), Gyllensten, U. (Ulf), Ohlsson, C. (Claes), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Perusse, L. (Louis), Wilson, J.F. (James), Hayward, C. (Caroline), Polasek, O. (Ozren), Cucca, F. (Francesco), Hveem, K. (Kristian), Hartman, C.A. (Catharina A.), Tönjes, A. (Anke), Bandinelli, S. (Stefania), Palmer, L.J. (Lyle J.), Kardia, S.L.R. (Sharon L. R.), Rauramaa, R. (Rainer), Sørensen, T.I.A. (Thorkild), Tuomilehto, J. (Jaakko), Salomaa, V. (Veikko), Penninx, B.W.J.H. (Brenda), Geus, E.J.C. (Eco) de, Boomsma, D.I. (Dorret), Lehtimäki, T. (Terho), Mangino, M. (Massimo), Laakso, M. (Markku), Bouchard, C. (Claude), Martin, N.G. (Nicholas), Kuh, D. (Diana), Liu, Y. (YongMei), Linneberg, A. (Allan), März, W. (Winfried), Strauch, K. (Konstantin), Kivimaki, M. (Mika), Harris, T.B. (Tamara), Gudnason, V. (Vilmundur), Völzke, H. (Henry), Qi, L. (Lu), Jarvelin, M.-R. (Marjo-Riitta), Chambers, J.C. (John), Kooner, J.S. (Jaspal S.), Froguel, P. (Philippe), Kooperberg, C. (Charles), Vollenweider, P. (Peter), Hallmans, G. (Göran), Hansen, T. (T.), Pedersen, O. (Oluf), Metspalu, A. (Andres), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Weir, D.R. (David), Porteous, D.J. (David J.), Boerwinkle, E.A. (Eric), Chasman, D.I. (Daniel), Abecasis, G.R. (Gonçalo R.), Barroso, I.E. (Inês), McCarthy, M.I. (Mark I.), Frayling, T.M. (Timothy), O’Connell, J.R. (Jeffrey R.), Duijn, C.M. (Cornelia) van, Boehnke, M. (Michael), Heid, I.M. (Iris), Mohlke, K.L. (Karen), Strachan, D.P. (David), Fox, C.S. (Caroline), Liu, C.-T. (Ching-Ti), Hirschhorn, J.N. (Joel), Klein, R.J. (Robert J.), Johnson, A.D. (Andrew), Borecki, I.B. (Ingrid), Franks, P.W. (Paul), North, K.E. (Kari), Cupples, L.A. (Adrienne), Loos, R.J.F. (Ruth), and Kilpeläinen, T.O. (Tuomas)
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Published: 2017
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50. Genome-wide association study implicates atrial natriuretic peptide rather than B-type natriuretic peptide in the regulation of blood pressure in the general population

Author: Salo, P. P. (Perttu P.), Havulinna, A. S. (Aki S.), Tukiainen, T. (Taru), Raitakari, O. (Olli), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Kettunen, J. (Johannes), Männikkö, M. (Minna), Eriksson, J. G. (Johan G.), Jula, A. (Antti), Blankenberg, S. (Stefan), Zeller, T. (Tanja), Salomaa, V. (Veikko), Kristiansson, K. (Kati), Perola, M. (Markus), Salo, P. P. (Perttu P.), Havulinna, A. S. (Aki S.), Tukiainen, T. (Taru), Raitakari, O. (Olli), Lehtimäki, T. (Terho), Kähönen, M. (Mika), Kettunen, J. (Johannes), Männikkö, M. (Minna), Eriksson, J. G. (Johan G.), Jula, A. (Antti), Blankenberg, S. (Stefan), Zeller, T. (Tanja), Salomaa, V. (Veikko), Kristiansson, K. (Kati), and Perola, M. (Markus)
Abstract: Background: Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP. Methods and Results: We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide–associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (NPPA-NPPB and POC1B-GALNT4) and 1 novel locus (PPP3CC) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The NPPA-NPPB locus containing the adjacent genes encoding ANP and BNP harbored 4 independent cis variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene PPP3CC and the polypeptide N-acetylgalactosaminyltransferase 4 gene GALNT4 associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (P=8.2×10⁻⁴). Conclusions: Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure–lowering effect of ANP in the general population.
Published: 2017

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