Genetic architecture reconciles linkage and association studies of complex traits.

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
07 Oct 2024
Historique:
received: 26 02 2023
accepted: 30 08 2024
medline: 8 10 2024
pubmed: 8 10 2024
entrez: 7 10 2024
Statut: aheadofprint

Résumé

Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76 ± 0.05) and BMI (0.55 ± 0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci.

Identifiants

DOI: 10.1038/s41588-024-01940-2 PMID: 39375568
pubmed: 39375568
doi: 10.1038/s41588-024-01940-2
pii: 10.1038/s41588-024-01940-2
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Investigateurs

Ilja M Nolte (IM)

Informations de copyright

© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Julia Sidorenko (J)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. j.sidorenko@imb.uq.edu.au.
ORCID: 0000-0003-1494-6772

Baptiste Couvy-Duchesne (B)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Sorbonne University, Paris Brain Institute-ICM, CNRS, INRIA, INSERM, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France.

Kathryn E Kemper (KE)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
ORCID: 0000-0002-9288-4522

Gunn-Helen Moen (GH)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia.

Laxmi Bhatta (L)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Bjørn Olav Åsvold (BO)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway.
ORCID: 0000-0003-3837-2101

Reedik Mägi (R)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Alireza Ani (A)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
ORCID: 0000-0002-7868-3118

Rujia Wang (R)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0003-2574-990X

Ilja M Nolte (IM)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
ORCID: 0000-0001-5047-4077

Scott Gordon (S)

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
ORCID: 0000-0001-7623-328X

Caroline Hayward (C)

MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
ORCID: 0000-0002-9405-9550

Archie Campbell (A)

Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
ORCID: 0000-0003-0198-5078

Daniel J Benjamin (DJ)

Human Genetics Department, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Behavioral Decision Making Group, Anderson School of Management, University of California Los Angeles, Los Angeles, CA, USA.
National Bureau of Economic Research, Cambridge, MA, USA.
ORCID: 0000-0002-2642-5416

David Cesarini (D)

National Bureau of Economic Research, Cambridge, MA, USA.
Department of Economics, New York University, New York, NY, USA.
Center for Experimental Social Science, New York University, New York, NY, USA.
ORCID: 0000-0002-0043-009X

David M Evans (DM)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
ORCID: 0000-0003-0663-4621

Michael E Goddard (ME)

Centre for AgriBioscience, Agriculture Victoria, Bundoora, Victoria, Australia.
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.

Chris S Haley (CS)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK.
Coupland Craft Cider, Coupland, Northumberland, UK.

David Porteous (D)

MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
ORCID: 0000-0003-1249-6106

Sarah E Medland (SE)

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
ORCID: 0000-0003-1382-380X

Nicholas G Martin (NG)

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
ORCID: 0000-0003-4069-8020

Harold Snieder (H)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0003-1949-2298

Andres Metspalu (A)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
ORCID: 0000-0002-3718-796X

Kristian Hveem (K)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.

Ben Brumpton (B)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
ORCID: 0000-0002-3058-1059

Peter M Visscher (PM)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, UK. peter.visscher@uq.edu.au.
ORCID: 0000-0002-2143-8760

Loic Yengo (L)

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. l.yengo@imb.uq.edu.au.

Classifications MeSH