|
|
| PMID |
|
|
| TITLE |
|
| Genetic architecture reconciles linkage and association studies of complex traits. |
|
| ABSTRACT |
|
|
|
| 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. |
| © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2023/02/26 |
| accepted |
2024/08/30 |
| medline |
2024/11/13 13:56 |
| pubmed |
2024/10/08 00:23 |
| entrez |
2024/10/07 23:39 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Sidorenko J |
|
Sidorenko |
Julia |
J |
|
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. j.sidorenko@imb.uq.edu.au. |
| Couvy-Duchesne B |
|
Couvy-Duchesne |
Baptiste |
B |
|
Sorbonne University, Paris Brain Institute-ICM, CNRS, INRIA, INSERM, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France. |
| Kemper KE |
|
Kemper |
Kathryn E |
KE |
|
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. |
| Moen GH |
|
Moen |
Gunn-Helen |
GH |
|
The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia. |
| Bhatta L |
|
Bhatta |
Laxmi |
L |
|
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. |
| Åsvold BO |
|
Åsvold |
Bjørn Olav |
BO |
|
Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway. |
| Mägi R |
|
Mägi |
Reedik |
R |
|
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
|
Estonian Biobank Research Team |
|
|
|
|
|
| Ani A |
|
Ani |
Alireza |
A |
|
Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran. |
| Wang R |
|
Wang |
Rujia |
R |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. |
| Nolte IM |
|
Nolte |
Ilja M |
IM |
|
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
|
Lifelines Cohort Study |
|
|
|
|
|
| Gordon S |
|
Gordon |
Scott |
S |
|
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Hayward C |
|
Hayward |
Caroline |
C |
|
MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK. |
| Campbell A |
|
Campbell |
Archie |
A |
|
Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK. |
| Benjamin DJ |
|
Benjamin |
Daniel J |
DJ |
|
National Bureau of Economic Research, Cambridge, MA, USA. |
| Cesarini D |
|
Cesarini |
David |
D |
|
Center for Experimental Social Science, New York University, New York, NY, USA. |
| Evans DM |
|
Evans |
David M |
DM |
|
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. |
| Goddard ME |
|
Goddard |
Michael E |
ME |
|
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia. |
| Haley CS |
|
Haley |
Chris S |
CS |
|
Coupland Craft Cider, Coupland, Northumberland, UK. |
| Porteous D |
|
Porteous |
David |
D |
|
MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK. |
| Medland SE |
|
Medland |
Sarah E |
SE |
|
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Snieder H |
|
Snieder |
Harold |
H |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. |
| Metspalu A |
|
Metspalu |
Andres |
A |
|
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
| Hveem K |
|
Hveem |
Kristian |
K |
|
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway. |
| Brumpton B |
|
Brumpton |
Ben |
B |
|
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway. |
| Visscher PM |
|
Visscher |
Peter M |
PM |
|
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. |
| Yengo L |
|
Yengo |
Loic |
L |
|
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. l.yengo@imb.uq.edu.au. |
|
| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Nolte |
Ilja M |
IM |
|
|
| JOURNAL |
|
| VOLUME: 56 |
| ISSUE: 11 |
| TITLE: Nature genetics |
| ISOABBREVIATION: Nat Genet |
| YEAR: 2024 |
| MONTH: Nov |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1546-1718 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Nat Genet |
| COUNTRY: United States |
| ISSNLINKING: 1061-4036 |
| NLMUNIQUEID: 9216904 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
|
| Genome-Wide Association Study |
methods |
| Multifactorial Inheritance |
genetics |
| Genetic Linkage |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| Body Mass Index |
genetics |
| Body Height |
genetics |
| Quantitative Trait Loci |
genetics |
| Phenotype |
genetics |
| Siblings |
genetics |
| Male |
genetics |
| Female |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
|
| OTHER ID's |
|
|
|
