Within-sibship GWAS improve estimates of direct genetic effects
Laurence J. Howe,Michel G. Nivard,Tim T Morris,Ailin Falkmo Hansen,Humaira Rasheed,Yoonsu Cho,Geetha Chittoor,Penelope A. Lind,Penelope A. Lind,Penelope A. Lind,Teemu Palviainen,Matthijs D. van der Zee,Rosa Cheesman,Rosa Cheesman,Massimo Mangino,Yunzhang Wang,Shuai Li,Shuai Li,Shuai Li,Lucija Klaric,Scott M. Ratliff,Lawrence F. Bielak,Marianne Nygaard,Marianne Nygaard,Chandra A. Reynolds,Jared V. Balbona,Christopher R. Bauer,Dorret I. Boomsma,Aris Baras,Archie Campbell,Harry Campbell,Zhengming Chen,Paraskevi Christofidou,Christina C. Dahm,Deepika R Dokuru,Luke M. Evans,Eco J. C. de Geus,Eco J. C. de Geus,Sudheer Giddaluru,Sudheer Giddaluru,Scott D. Gordon,K. Paige Harden,Alexandra Havdahl,W. David Hill,Shona M. Kerr,Yongkang Kim,Hyeokmoon Kweon,Antti Latvala,Liming Li,Kuang Lin,Pekka Martikainen,Pekka Martikainen,Pekka Martikainen,Patrik K. E. Magnusson,Melinda Mills,Debbie A Lawlor,John D. Overton,Nancy L. Pedersen,David J. Porteous,Jeffrey S. Reid,Karri Silventoinen,Melissa C. Southey,Melissa C. Southey,Melissa C. Southey,Travis T. Mallard,Elliot M. Tucker-Drob,Margaret J. Wright,John K. Hewitt,Matthew C. Keller,Michael C. Stallings,Kaare Christensen,Kaare Christensen,Sharon L.R. Kardia,Patricia A. Peyser,Jennifer A. Smith,James F. Wilson,James F. Wilson,John L. Hopper,Sara Hägg,Tim D. Spector,Jean-Baptiste Pingault,Jean-Baptiste Pingault,Robert Plomin,Meike Bartels,Nicholas G. Martin,Anne E. Justice,Iona Y Millwood,Kristian Hveem,Øyvind Næss,Øyvind Næss,Cristen J. Willer,Cristen J. Willer,Bjørn Olav Åsvold,Philipp Koellinger,Philipp Koellinger,Jaakko Kaprio,Sarah E. Medland,Sarah E. Medland,Robin G. Walters,Daniel J. Benjamin,Daniel J. Benjamin,Patrick Turley,David M. Evans,David M. Evans,George Davey Smith,Caroline Hayward,Ben Michael Brumpton,Ben Michael Brumpton,Gibran Hemani,Neil M Davies,Neil M Davies +110 more
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In this article, the authors combined data on 159,701 siblings from 17 cohorts to generate population and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes.Abstract:
Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects, but large-scale family datasets have been lacking. We combined data on 159,701 siblings from 17 cohorts to generate population (between-family) and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes. We demonstrate that existing GWAS associations for height, educational attainment, smoking, depressive symptoms, age at first birth and cognitive ability overestimate direct effects. We show that estimates of SNP-heritability, genetic correlations and Mendelian randomization involving these phenotypes substantially differ when calculated using within-sibship estimates. For example, genetic correlations between educational attainment and height largely disappear. In contrast, analyses of most clinical phenotypes (e.g. LDL-cholesterol) were generally consistent between population and within-sibship models. We also report compelling evidence of polygenic adaptation on taller human height using within-sibship data. Large-scale family datasets provide new opportunities to quantify direct effects of genetic variation on human traits and diseases.read more
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Journal ArticleDOI
Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals
Aysu Okbay,Yeda Wu,Nancy Wang,Hariharan Jayashankar,Michael Bennett,Seyed Moeen Nehzati,Julia Sidorenko,Hyeokmoon Kweon,Grant Goldman,Tamara Gjorgjieva,Yunxuan Jiang,B. Hicks,Chao Tian,David A. Hinds,Rafael Ahlskog,Patrik K. E. Magnusson,Sven Oskarsson,Caroline Hayward,Archie Campbell,David J. Porteous,Jeremy Freese,Pamela Herd,Michelle Agee,Babak Alipanahi,Adam Auton,Robert K. Bell,Katarzyna Bryc,Sarah L. Elson,Pierre Fontanillas,Nicholas A. Furlotte,Karen E. Huber,Aaron Kleinman,Nadia K. Litterman,Jennifer C. McCreight,Matthew H. McIntyre,Joanna L. Mountain,Carrie A.M. Northover,Steven J. Pitts,J. Fah Sathirapongsasuti,Olga V. Sazonova,Janie F. Shelton,Suyash Shringarpure,Joyce Y. Tung,Vladimir Vacic,Catherine H. Wilson,Mark Alan Fontana,Tune H. Pers,Cornelius A. Rietveld,Guo-Bo Chen,Valur Emilsson,S. Fleur W. Meddens,Joseph K. Pickrell,Kevin Thom,Pascal Timshel,Ronald de Vlaming,Abdel Abdellaoui,Tarunveer S. Ahluwalia,Jonas Bacelis,Clemens Baumbach,Gyda Bjornsdottir,Johannes H. Brandsma,Maria Pina Concas,Jaime Derringer,Tessel E. Galesloot,Giorgia Girotto,Richa Gupta,Leanne M. Hall,Sarah E. Harris,Edith Hofer,Momoko Horikoshi,Jennifer E. Huffman,Kadri Kaasik,Ioanna P. Kalafati,Robert Karlsson,Jari Lahti,S. J. van der Lee,Christiaan de Leeuw,Penelope A. Lind,Karl-Oskar Lindgren,Tian Liu,Massimo Mangino,Jonathan Marten,Evelin Mihailov,Michael B. Miller,Peter J. van der Most,Christopher Oldmeadow,Antony Payton,Natalia Pervjakova,Wouter J. Peyrot,Yong-chao Qian,Olli T. Raitakari,Rico Rueedi,Erika Salvi,Börge Schmidt,Katharina E. Schraut,Jianxin Shi,Raymond A. Poot,Beate St Pourcain,Alexander Teumer,Gudmar Thorleifsson,Niek Verweij,Dragana Vuckovic,Juergen Wellmann,Harm-Jan Westra,Jingyun Yang,Wei Zhao,Zhihong Zhu,Behrooz Z. Alizadeh,Najaf Amin,Andrew Bakshi,Sebastian E. Baumeister,Ginevra Biino,Klaus Bønnelykke,Patricia A. Boyle,Harry Campbell,Francesco P. Cappuccio,Gail Davies,Jan-Emmanuel De Neve,Panos Deloukas,Ilja Demuth,Jun Ding,Peter Eibich,Lewin Eisele,Niina Eklund,David M. Evans,Jessica D. Faul,Mary F. Feitosa,Andreas J. Forstner,Ilaria Gandin,Bjarni Kristinn Gunnarsson,Bjarni V. Halldorsson,Tamara B. Harris,Andrew C. Heath,Lynne J. Hocking,Elizabeth G. Holliday,Georg Homuth,Michael A. Horan,Jouke-Jan Hottenga,Philip L. De Jager,Peter K. Joshi,Astanand Jugessur,Marika Kaakinen,Mika Kähönen,Stavroula Kanoni,Liisa Keltigangas-Jarvinen,Lambertus A. Kiemeney,Ivana Kolcic,Seppo Koskinen,Aldi T. Kraja,Martin Kroh,Zoltán Kutalik,Antti Latvala,Lenore J. Launer,Maël Lebreton,Douglas F. Levinson,Paul Lichtenstein,Peter Lichter,David C. Liewald,Anu Loukola,Pamela A. F. Madden,Reedik Mägi,Tomi Mäki-Opas,Riccardo E. Marioni,Pedro Marques-Vidal,Gerardus A. Meddens,George McMahon,Christa Meisinger,Thomas Meitinger,Y. Milaneschi,Lili Milani,Grant W. Montgomery,Ronny Myhre,Christopher P. Nelson,Dale R. Nyholt,William E R Ollier,Aarno Palotie,Lavinia Paternoster,Nancy L. Pedersen,K. Petrovic,Katri Räikkönen,Susan M. Ring,Antonietta Robino,Olga Rostapshova,Igor Rudan,Aldo Rustichini,Veikko Salomaa,Alan R. Sanders,Antti-Pekka Sarin,E. E. Schmidt,Rodney J. Scott,Blair H. Smith,Jennifer A. Smith,Jan A. Staessen,Elisabeth Steinhagen-Thiessen,Konstantin Strauch,Antonio Terracciano,Martin D. Tobin,Sheila Ulivi,Simona Vaccargiu,Lydia Quaye,Frank J. A. van Rooij,Cristina Venturini,Anna A. E. Vinkhuyzen,Uwe Völker,Henry Völzke,Judith M. Vonk,Diego Vozzi,Johannes Waage,Erin B. Ware,Gonneke Willemsen,J. Attia,David A. Bennett,Klaus Berger,Lars Bertram,Hans Bisgaard,Dorret I. Boomsma,Ingrid B. Borecki,Ute Bültmann,Christopher F. Chabris,Francesco Cucca,Daniele Cusi,Ian J. Deary,George Dedoussis,Cornelia M. van Duijn,Johan G. Eriksson,Barbara Franke,Lude Franke,Paolo Gasparini,Pablo V. Gejman,Christian Gieger,Hans J. Grabe,Jacob Gratten,Patrick J. F. Groenen,Vilmundur Gudnason,P. Van der Harst,Wolfgang Hoffmann,Elina Hyppönen,William G. Iacono,Bo Jacobsson,Marjo-Riitta Järvelin,Karl-Heinz Jöckel,Jaakko Kaprio,Sharon L.R. Kardia,Terho Lehtimäki,Steven F. Lehrer,Nicholas G. Martin,Matt McGue,Andres Metspalu,Neil Pendleton,Brenda W.J.H. Penninx,Markus Perola,Nicola Pirastu,Mario Pirastu,Ozren Polasek,Danielle Posthuma,Christine Power,Michael A. Province,Nilesh J. Samani,David Schlessinger,Reinhold Schmidt,Thorkild I. A. Sørensen,Tim D. Spector,Kari Stefansson,Unnur Thorsteinsdottir,Roy Thurik,Nicholas J. Timpson,Henning Tiemeier,André G. Uitterlinden,Veronique Vitart,Peter Vollenweider,David R. Weir,James F. Wilson,Alan F. Wright,R. Kroeger,George Davey Smith,Albert Hofman,David Laibson,Sarah E. Medland,Jian Yang,Tõnu Esko,Chelsea Coleman Watson,Jonathan B. Jala,Dalton Conley,Philipp Koellinger,Magnus Johannesson,Michelle N. Meyer,James J. Lee,Augustine Kong,Loic Yengo,David Cesarini,Patrick Turley,Peter M. Visscher,Jonathan P. Beauchamp,Daniel J. Benjamin,Alexander I. Young +294 more
TL;DR: This paper conducted a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identified 3,952 approximately uncorrelated single-nucleotide polymorphisms (SNPs).
Journal ArticleDOI
Dissecting polygenic signals from genome-wide association studies on human behaviour.
TL;DR: Abdellaoui et al. as discussed by the authors showed that the results of genome-wide association studies for human behaviour are likely made up of a composite of signals from different sources.
Journal ArticleDOI
Utility of polygenic embryo screening for disease depends on the selection strategy.
Todd Lencz,Todd Lencz,Daniel Backenroth,Einat Granot-Hershkovitz,Adam W. Green,Kyle Gettler,Judy H. Cho,Omer Weissbrod,Or Zuk,Shai Carmi +9 more
TL;DR: In this article, the authors predict the expected reduction in complex disease risk following polygenic embryo screening for a single disease, based on the liability threshold model, and examine the impact of several factors on the utility of screening, including: variance explained by the PRS, number of embryos, disease prevalence, parental PRSs and parental disease status.
Posted ContentDOI
Utility of polygenic embryo screening for disease depends on the selection strategy
TL;DR: The main finding is that a strong determinant of the potential utility of polygenic embryo screening is the selection strategy, a factor that has not been previously studied.
Journal ArticleDOI
Using Mendelian randomization analysis to better understand the relationship between mental health and substance use: a systematic review.
TL;DR: For instance, this paper assessed the evidence for causal relationships between mental health and substance use from Mendelian randomization (MR) studies, following PRISMA, and found that higher educational attainment decreases smoking and that there is a bi-directional, increasing relationship between smoking and (symptoms of) mental disorders.
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