Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
Laurence J. Howe(Bristol City Council), Michel G. Nivard(Vrije Universiteit Amsterdam), Tim Morris(University of Bristol), Ailin Falkmo Hansen(Norwegian University of Science and Technology), Humaira Rasheed(Norwegian University of Science and Technology), Yoonsu Cho(University of Bristol), Geetha Chittoor(Geisinger Health System), Rafael Ahlskog(Uppsala University), Penelope A. Lind(Queensland University of Technology), Teemu Palviainen(University of Helsinki), Matthijs D. van der Zee(Vrije Universiteit Amsterdam), Rosa Cheesman(King's College London), Massimo Mangino(King's College London), Yunzhang Wang(Karolinska Institutet), Shuai Li(The University of Melbourne), Lucija Klaric(Western General Hospital), Scott M. Ratliff(University of Michigan), Lawrence F. Bielak(University of Michigan), Marianne Nygaard(University of Southern Denmark), Alexandros Giannelis(University of Minnesota), Emily A. Willoughby(University of Minnesota), Chandra A. Reynolds(University of California, Riverside), Jared V. Balbona(University of Colorado Boulder), Ole A. Andreassen(Oslo University Hospital), Helga Ask(Norwegian Institute of Public Health), Aris Baras(Regeneron (United States)), Christopher R. Bauer(Geisinger Health System), Dorret I. Boomsma(GGD Amsterdam), Archie Campbell(Western General Hospital), Harry Campbell(University of Edinburgh), Zhengming Chen(University of Oxford), Paraskevi Christofidou(King's College London), Elizabeth C. Corfield(Norwegian Institute of Public Health), Christina C. Dahm(Aarhus University), Deepika Dokuru(University of Colorado Boulder), Luke M. Evans(University of Colorado Boulder), Eco J. C. de Geus(Amsterdam University Medical Centers), Sudheer Giddaluru(Norwegian Institute of Public Health), Scott D. Gordon(QIMR Berghofer Medical Research Institute), K. Paige Harden(The University of Texas at Austin), W. David Hill(NHS Lothian), Amanda Hughes(University of Bristol), Shona M. Kerr(Western General Hospital), Yongkang Kim(University of Colorado Boulder), Hyeokmoon Kweon(Vrije Universiteit Amsterdam), Antti Latvala(University of Helsinki), Debbie A. Lawlor(University of Bristol), Liming Li(Peking University), Kuang Lin(University of Oxford), Per Magnus(Norwegian Institute of Public Health), Patrik K. E. Magnusson(Karolinska Institutet), Travis T. Mallard(The University of Texas at Austin), Pekka Martikainen(University of Helsinki), Melinda C. Mills(Leverhulme Trust), Pål R. Njølstad(Haukeland University Hospital), John D. Overton(Regeneron (United States)), Nancy L. Pedersen(Karolinska Institutet), David J. Porteous(Western General Hospital), Jeffrey G. Reid(Regeneron (United States)), Karri Silventoinen(University of Helsinki), Melissa C. Southey(The University of Melbourne), Camilla Stoltenberg(Norwegian Institute of Public Health), Elliot M. Tucker–Drob(The University of Texas at Austin), Margaret J. Wright(The University of Queensland), Hyeokmoon Kweon(Vrije Universiteit Amsterdam), Philipp Koellinger(University of Wisconsin–Madison), Daniel J. Benjamin(National Bureau of Economic Research), Patrick Turley(University of Southern California), Laurence J. Howe(Bristol City Council), Michel G. Nivard(Vrije Universiteit Amsterdam), Tim Morris(University of Bristol), Ailin Falkmo Hansen(Norwegian University of Science and Technology), Humaira Rasheed(Norwegian University of Science and Technology), Yoonsu Cho(University of Bristol), Geetha Chittoor(Geisinger Health System), Rafael Ahlskog(Uppsala University), Penelope A. Lind(Queensland University of Technology), Teemu Palviainen(University of Helsinki), Matthijs D. van der Zee(Vrije Universiteit Amsterdam), Rosa Cheesman(King's College London), Massimo Mangino(King's College London), Yunzhang Wang(Karolinska Institutet), Shuai Li(The University of Melbourne), Lucija Klaric(Western General Hospital), Scott M. Ratliff(University of Michigan), Lawrence F. Bielak(University of Michigan), Marianne Nygaard(University of Southern Denmark), Alexandros Giannelis(University of Minnesota), Emily A. Willoughby(University of Minnesota), Chandra A. Reynolds(University of California, Riverside), Jared V. Balbona(University of Colorado Boulder), Ole A. Andreassen(Oslo University Hospital), Helga Ask(Norwegian Institute of Public Health), Dorret I. Boomsma(GGD Amsterdam), Archie Campbell(Western General Hospital), Harry Campbell(University of Edinburgh), Zhengming Chen(University of Oxford), Paraskevi Christofidou(King's College London), Elizabeth C. Corfield(Norwegian Institute of Public Health), Christina C. Dahm(Aarhus University), Deepika Dokuru(University of Colorado Boulder), Luke M. Evans(University of Colorado Boulder), Eco J. C. de Geus(Amsterdam University Medical Centers), Sudheer Giddaluru(Norwegian Institute of Public Health), Scott D. Gordon(QIMR Berghofer Medical Research Institute), K. Paige Harden(The University of Texas at Austin), W. David Hill(NHS Lothian), Amanda Hughes(University of Bristol), Shona M. Kerr(Western General Hospital), Yongkang Kim(University of Colorado Boulder), Antti Latvala(University of Helsinki), Deborah A. Lawlor(University of Bristol), Liming Li(Peking University), Kuang Lin(University of Oxford), Per Magnus(Norwegian Institute of Public Health), Patrik K. E. Magnusson(Karolinska Institutet), Travis T. Mallard(The University of Texas at Austin), Pekka Martikainen(University of Helsinki), Melinda C. Mills(Leverhulme Trust), Pål R. Njølstad(Haukeland University Hospital), Nancy L. Pedersen(Karolinska Institutet), David J. Porteous(Western General Hospital), Karri Silventoinen(University of Helsinki), Melissa C. Southey(The University of Melbourne), Camilla Stoltenberg(Norwegian Institute of Public Health), Elliot M. Tucker–Drob(The University of Texas at Austin), Margaret J. Wright(The University of Queensland), John K. Hewitt(University of Colorado Boulder), Matthew C. Keller(University of Colorado Boulder), Michael C. Stallings(University of Colorado Boulder), James J. Lee(University of Minnesota), Kaare Christensen(University of Southern Denmark), Sharon L. R. Kardia(University of Michigan), Patricia A. Peyser(University of Michigan), Jennifer A. Smith(University of Michigan), James F. Wilson(Western General Hospital), John L. Hopper(The University of Melbourne), Sara Hägg(Karolinska Institutet), Tim D. Spector(King's College London), Jean‐Baptiste Pingault(King's College London), Robert Plomin(King's College London), Alexandra Havdahl(Norwegian Institute of Public Health), Meike Bartels(Vrije Universiteit Amsterdam), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Sven Oskarsson(Uppsala University), Anne E. Justice(University of Oxford), Iona Y. Millwood(Norwegian University of Science and Technology), Kristian Hveem(Norwegian Institute of Public Health), Øyvind Næss(Norwegian Institute of Public Health), Cristen J. Willer(Norwegian University of Science and Technology), Bjørn Olav Åsvold(University of Helsinki), Jaakko Kaprio(University of Helsinki), Sarah E. Medland(The University of Queensland), Robin Walters(The University of Queensland), David M. Evans(The University of Queensland), George Davey Smith(Western General Hospital), Caroline Hayward(Norwegian University of Science and Technology), Ben Brumpton(Norwegian University of Science and Technology), Gibran Hemani(Bristol City Council), Neil M Davies(University of Colorado Boulder), John K. Hewitt(University of Colorado Boulder), Matthew C. Keller(University of Colorado Boulder), Michael C. Stallings(University of Minnesota), James J. Lee(University of Minnesota), Kaare Christensen(University of Southern Denmark), Sharon L. R. Kardia(University of Michigan), Patricia A. Peyser(University of Michigan), Jennifer A. Smith(University of Michigan), James F. Wilson(The University of Melbourne), John L. Hopper(The University of Melbourne), Sara Hägg(King's College London), Tim D. Spector(King's College London), Jean‐Baptiste Pingault(King's College London), Robert Plomin(King's College London), Alexandra Havdahl(Norwegian Institute of Public Health), Meike Bartels(QIMR Berghofer Medical Research Institute), Nicholas G. Martin(Uppsala University), Sven Oskarsson(Uppsala University), Anne E. Justice(University of Oxford), Iona Y. Millwood(Norwegian University of Science and Technology), Kristian Hveem(Norwegian Institute of Public Health), Øyvind Næss(Norwegian Institute of Public Health), Cristen J. Willer(Norwegian University of Science and Technology), Bjørn Olav Åsvold(University of Wisconsin–Madison), Philipp Koellinger(University of Helsinki), Jaakko Kaprio(University of Helsinki), Sarah E. Medland(The University of Queensland), Robin Walters(National Bureau of Economic Research), Daniel J. Benjamin(University of Southern California), Patrick Turley(University of Southern California), David M. Evans(The University of Queensland), George Davey Smith(Western General Hospital), Caroline Hayward(Norwegian University of Science and Technology), Ben Brumpton(Norwegian University of Science and Technology), Gibran Hemani(Norwegian University of Science and Technology), Neil M Davies(Norwegian University of Science and Technology)
Cited by 390Open Access
Abstract
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
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