Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
41282763
TITLE
Family-GWAS reveals effects of environment and mating on genetic associations.
ABSTRACT
Genome-wide association studies (GWAS) have discovered thousands of replicable genetic associations, guiding drug target discovery and powering genetic prediction of human phenotypes and diseases. However, genetic associations can be affected by gene-environment correlations and non-random mating, which can lead to biased inferences in downstream analyses. Family-based GWAS (FGWAS) uses the natural experiment of random assignment of genotype within families to separate out the contribution of direct genetic effects (DGEs) - causal effects of alleles in an individual on an individual - from other factors contributing to genetic associations. Here, we report results from an FGWAS meta-analysis of 34 phenotypes from 17 cohorts. We found evidence that factors uncorrelated with DGEs make substantial contributions to genetic associations for 27 phenotypes, with population stratification confounding - a form of gene-environment correlation - likely the major cause. By estimating SNP heritability and genetic correlations using DGEs, we found evidence that assortative mating has led to overestimation of SNP heritability for 5 phenotypes and overestimation of the degree of shared genetic effects (pleiotropy) between 22 pairs of phenotypes. Polygenic predictors constructed from DGEs are particularly useful for studying natural selection, assortative mating, and indirect genetic effects (effects of relatives' genes mediated through the family environment). We validate our meta-analysis results by predicting phenotypes in hold-out samples using polygenic predictors constructed from DGEs, achieving statistically significant out-of-sample prediction for 24 phenotypes with little attenuation of predictive power within-families. We provide FGWAS summary statistics for 34 phenotypes that can be used for downstream analyses. Our study provides both a template for performing FGWAS and an argument for its value for debiasing inferences and understanding the impact of environment and mating patterns.
DATE PUBLISHED
2025 Oct 14
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2025/11/24 18:21
medline 2025/11/24 12:40
entrez 2025/11/24 09:16
pmc-release 2025/11/20
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Tan T Tan Tammy T National Bureau of Economic Research, Cambridge, MA, USA.
Jayashankar H Jayashankar Hariharan H UCLA Anderson School of Management, Los Angeles, CA, USA.
Guan J Guan Junming J UCLA Anderson School of Management, Los Angeles, CA, USA.
Nehzati SM Nehzati Seyed Moeen SM UCLA Anderson School of Management, Los Angeles, CA, USA.
Mir M Mir Mahdi M UCLA Anderson School of Management, Los Angeles, CA, USA.
Bennett M Bennett Michael M National Bureau of Economic Research, Cambridge, MA, USA.
Agerbo E Agerbo Esben E National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
Ahlskog R Ahlskog Rafael R Department of Government, Uppsala university.
Pinto de Andrade Anapaz V Pinto de Andrade Anapaz Ville V Institute for Molecular Medicine Finland FIMM, HILife, University of Helsinki, Helsinki, FIN-00140 Finland.
Åsvold BO Åsvold Bjørn Olav BO Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, 7006, Norway.
Benonisdottir S Benonisdottir Stefania S Big Data Institute, Li Ka Shing Centre for Health Information Discovery, University of Oxford, Oxford OX3 7LF, UK.
Bhatta L Bhatta Laxmi L FIU-PH, Division of Mental Health Care, St. Olavs Hospital, Trondheim, Norway.
Boomsma DI Boomsma Dorret I DI Department of Complex Traits Genetics CNCR, Vrije Universiteit Amsterdam, De Boelelaan 1105 1081 HV Amsterdam, The Netherlands.
Brumpton B Brumpton Ben B Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7030, Norway.
Campbell A Campbell Archie A Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh Bioquarter, 5-7 Little France Road, Edinburgh, EH16 4UX, United Kingdom.
Chabris CF Chabris Christopher F CF Department of Bioethics & Decision Sciences, Geisinger Health System, 100 North Academy Avenue, Danville, PA 17822 USA.
Cheesman R Cheesman Rosa R PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
Chen Z Chen Zhengming Z Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK.
China Kadoorie Biobank Collaborative Group
de Geus E de Geus Eco E Amsterdam Public Health Research Institute, VU Medical Center, De Boelelaan 1117 1081 HV Amsterdam, the Netherlands.
Ehli EA Ehli Erik A EA Avera Genetics, Avera McKennan Hospital & University Health Center, Sioux Falls, SD 57105, USA.
Elnahas AG Elnahas Abdelrahman G AG Institute of Genomics, University of Tartu, Tartu, Estonia.
Estonian Biobank Research Team
Finngen
Ganna A Ganna Andrea A Analytic & Translational Genetics Unit, Massachusetts General Hospital, Boston, USA.
Giannelis A Giannelis Alexandros A Department of Psychology, University of Minnesota Twin Cities, 75 East River Road, Minneapolis, MN 55455, USA.
Hakaste L Hakaste Liisa L Folkhalsan Research Center, Helsinki, FIN-00140 FInland.
Hansen AF Hansen Ailin Falkmo AF HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, 7030, Norway.
Havdahl A Havdahl Alexandra A PsychGen Centre for Genetic Epidemiology and Mental Health, Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway.
Hayward C Hayward Caroline C MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
Hottenga JJ Hottenga Jouke-Jan JJ Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, De Boelelaan 1105 1081 HV Amsterdam, The Netherlands.
Houmark MA Houmark Mikkel Aagaard MA Department of Economics and Business Economics and TrygFonden's Centre for Child Research, Aarhus University, Fuglesangs Allé 4, 8210 Aarhus V, Denmark.
Hveem K Hveem Kristian K HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, 7600, Norway.
Kaprio J Kaprio Jaakko J Institute for Molecular Medicine Finland FIMM, HILife, University of Helsinki, Helsinki, FIN-00140 Finland.
Langhammer A Langhammer Arnulf A HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, 7600, Norway.
Latvala A Latvala Antti A Institute of Criminology and Legal Policy, University of Helsinki.
Lee JJ Lee James J JJ Department of Psychology, University of Minnesota Twin Cities, 75 East River Road, Minneapolis, MN 55455, USA.
Lehtovirta M Lehtovirta Mikko M Institute for Molecular Medicine Finland FIMM, HILife, University of Helsinki, Helsinki, FIN-00140 Finland.
Li L Li Liming L Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, 100191, Beijing, China.
LifeLines Cohort Study
Lin K Lin Kuang K Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK.
Linnér RK Linnér Richard Karlsson RK School of Business and Economics, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, the Netherlands.
Lombardi S Lombardi Stefano S VATT Institute for Economic Research, Finland.
Martin NG Martin Nicholas G NG Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
McGue M McGue Matt M Department of Psychology, University of Minnesota Twin Cities, 75 East River Road, Minneapolis, MN 55455, USA.
Medland SE Medland Sarah E SE Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Metspalu A Metspalu Andres A Estonian Biobank Research Team: Andres Metspalu, Mari Nelis, Lili Milani, Reedik Mägi, Georgi Hudjashov & Tõnu Esko.
Mitchell BL Mitchell Brittany L BL Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Ni G Ni Guiyan G Institute for Molecular Bioscience, University of Queensland, Australia.
Nolte IM Nolte Ilja M IM Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Oetjens MT Oetjens Matthew T MT Autism and Developmental Medicine Institute, Geisinger Health System, 120 Hamm Drive, Lewisburg, PA 17837, USA.
Oskarsson S Oskarsson Sven S Department of Government, Uppsala university.
Palviainen T Palviainen Teemu T Institute for Molecular Medicine Finland FIMM, HILife, University of Helsinki, Helsinki, FIN-00140 Finland.
Prasad RB Prasad Rashmi B RB Lund University Diabetes Centre, Malmo, Sweden.
Reigo A Reigo Anu A Institute of Genomics, University of Tartu, Tartu, Estonia.
Reis K Reis Kadri K Institute of Genomics, University of Tartu, Tartu, Estonia.
Sidorenko J Sidorenko Julia J Institute for Molecular Bioscience, University of Queensland, Australia.
Silventoinen K Silventoinen Karri K Helsinki Institute for Demography and Population Health, University of Helsinki, Helsinki, Finland.
Snieder H Snieder Harold H Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Tuomi T Tuomi Tiinamaija T Endocrinology, Abdominal Centre, Helsinki University Hospital, Po Box 340, FIN-0029, Helsinki, Finland.
Vilhjálmsson BJ Vilhjálmsson Bjarni J BJ Novo Nordisk Foundation Center for Genomics Mechanisms of Disease, the Broad Institute of MIT and Harvard.
Walters RG Walters Robin G RG Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK.
Willoughby EA Willoughby Emily A EA Department of Psychology, University of Minnesota Twin Cities, 75 East River Road, Minneapolis, MN 55455, USA.
Winsvold BS Winsvold Bendik S BS Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
Ystrom E Ystrom Eivind E PsychGen Centre for Genetic Epidemiology and Mental Health, Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway.
Flint J Flint Jonathan J UCLA Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA.
Yengo L Yengo Loic L Institute for Molecular Bioscience, University of Queensland, Australia.
Visscher PM Visscher Peter M PM Institute for Molecular Bioscience, University of Queensland, Australia.
Kong A Kong Augustine A Leverhulme Centre for Demographic Science, Nuffield Department of Population Health, University of Oxford and Nuffield College, UK.
Tucker-Drob EM Tucker-Drob Elliot M EM Department of Psychology, The University of Texas at Austin, 108 E. Dean Keeton Stop A8000, Austin, TX 78712, USA.
Border R Border Richard R Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095.
Cesarini D Cesarini David D Research Institute of Industrial Economics (IFN), Stockholm, Sweden.
Turley P Turley Patrick P Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA.
Okbay A Okbay Aysu A Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Benjamin DJ Benjamin Daniel J DJ Human Genetics Department, UCLA David Geffen School of Medicine, Los Angeles, CA, US.
Young AS Young Alexander Strudwick AS Human Genetics Department, UCLA David Geffen School of Medicine, Los Angeles, CA, US.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: medRxiv : the preprint server for health sciences
ISOABBREVIATION: medRxiv
YEAR: 2025
MONTH: Oct
DAY: 14
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN:
ISSNTYPE:
MEDLINE JOURNAL
MEDLINETA: medRxiv
COUNTRY: United States
ISSNLINKING:
NLMUNIQUEID: 101767986
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Journal Article
Preprint
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R00 AG062787 NIA NIH HHS United States
R01 AG042568 NIA NIH HHS United States
R01 AG083379 NIA NIH HHS United States
R24 AG065184 NIA NIH HHS United States
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