Genetic architecture reconciles linkage and association studies of complex traits

Estonian Biobank Research Team; Lifelines Cohort Study; Julia Sidorenko; Baptiste Couvy-Duchesne; Kathryn E. Kemper; Gunn Helen Moen; Laxmi Bhatta; Bjørn Olav Åsvold; Reedik Mägi; Alireza Ani; Rujia Wang; Ilja M. Nolte; Scott Gordon; Caroline Hayward; Archie Campbell; Daniel J. Benjamin; David Cesarini; David M. Evans; Michael E. Goddard; Chris S. Haley; David Porteous; Sarah E. Medland; Nicholas G. Martin; Harold Snieder; Andres Metspalu; Kristian Hveem; Ben Brumpton; Peter M. Visscher; Loic Yengo

doi:10.1038/s41588-024-01940-2

Genetic architecture reconciles linkage and association studies of complex traits

Estonian Biobank Research Team, Lifelines Cohort Study, Julia Sidorenko^*, Baptiste Couvy-Duchesne, Kathryn E. Kemper, Gunn Helen Moen, Laxmi Bhatta, Bjørn Olav Åsvold, Reedik Mägi, Alireza Ani, Rujia Wang, Ilja M. Nolte, Scott Gordon, Caroline Hayward, Archie Campbell, Daniel J. Benjamin, David Cesarini, David M. Evans, Michael E. Goddard, Chris S. HaleyDavid Porteous, Sarah E. Medland, Nicholas G. Martin, Harold Snieder, Andres Metspalu, Kristian Hveem, Ben Brumpton, Peter M. Visscher^*, Loic Yengo^*

^*Corresponding author for this work

Life Course Epidemiology (LCE)

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	2352–2360
Number of pages	20
Journal	Nature genetics
Volume	56
Early online date	7-Oct-2024
DOIs	https://doi.org/10.1038/s41588-024-01940-2
Publication status	Published - Nov-2024

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Estonian Biobank Research Team, Lifelines Cohort Study, Sidorenko, J., Couvy-Duchesne, B., Kemper, K. E., Moen, G. H., Bhatta, L., Åsvold, B. O., Mägi, R., Ani, A., Wang, R., Nolte, I. M., Gordon, S., Hayward, C., Campbell, A., Benjamin, D. J., Cesarini, D., Evans, D. M., Goddard, M. E., ... Yengo, L. (2024). Genetic architecture reconciles linkage and association studies of complex traits. Nature genetics, 56, 2352–2360. https://doi.org/10.1038/s41588-024-01940-2

@article{53bb29b3183144f2a302fb554d5af664,

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.",

author = "{Estonian Biobank Research Team} and {Lifelines Cohort Study} and Julia Sidorenko and Baptiste Couvy-Duchesne and Kemper, {Kathryn E.} and Moen, {Gunn Helen} and Laxmi Bhatta and {\AA}svold, {Bj{\o}rn Olav} and Reedik M{\"a}gi and Alireza Ani and Rujia Wang and Nolte, {Ilja M.} and Scott Gordon and Caroline Hayward and Archie Campbell and Benjamin, {Daniel J.} and David Cesarini and Evans, {David M.} and Goddard, {Michael E.} and Haley, {Chris S.} and David Porteous and Medland, {Sarah E.} and Martin, {Nicholas G.} and Harold Snieder and Andres Metspalu and Kristian Hveem and Ben Brumpton and Visscher, {Peter M.} and Loic Yengo",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = nov,

doi = "10.1038/s41588-024-01940-2",

language = "English",

volume = "56",

pages = "2352–2360",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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Estonian Biobank Research Team, Lifelines Cohort Study, Sidorenko, J, Couvy-Duchesne, B, Kemper, KE, Moen, GH, Bhatta, L, Åsvold, BO, Mägi, R, Ani, A , Wang, R , Nolte, IM, Gordon, S, Hayward, C, Campbell, A, Benjamin, DJ, Cesarini, D, Evans, DM, Goddard, ME, Haley, CS, Porteous, D, Medland, SE, Martin, NG, Snieder, H, Metspalu, A, Hveem, K, Brumpton, B, Visscher, PM & Yengo, L 2024, 'Genetic architecture reconciles linkage and association studies of complex traits', Nature genetics, vol. 56, pp. 2352–2360. https://doi.org/10.1038/s41588-024-01940-2

TY - JOUR

T1 - Genetic architecture reconciles linkage and association studies of complex traits

AU - Estonian Biobank Research Team

AU - Lifelines Cohort Study

AU - Sidorenko, Julia

AU - Couvy-Duchesne, Baptiste

AU - Kemper, Kathryn E.

AU - Moen, Gunn Helen

AU - Bhatta, Laxmi

AU - Åsvold, Bjørn Olav

AU - Mägi, Reedik

AU - Ani, Alireza

AU - Wang, Rujia

AU - Nolte, Ilja M.

AU - Gordon, Scott

AU - Hayward, Caroline

AU - Campbell, Archie

AU - Benjamin, Daniel J.

AU - Cesarini, David

AU - Evans, David M.

AU - Goddard, Michael E.

AU - Haley, Chris S.

AU - Porteous, David

AU - Medland, Sarah E.

AU - Martin, Nicholas G.

AU - Snieder, Harold

AU - Metspalu, Andres

AU - Hveem, Kristian

AU - Brumpton, Ben

AU - Visscher, Peter M.

AU - Yengo, Loic

PY - 2024/11

Y1 - 2024/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85205797116&partnerID=8YFLogxK

U2 - 10.1038/s41588-024-01940-2

DO - 10.1038/s41588-024-01940-2

M3 - Article

C2 - 39375568

AN - SCOPUS:85205797116

SN - 1061-4036

VL - 56

SP - 2352

EP - 2360

JO - Nature genetics

JF - Nature genetics

ER -

Genetic architecture reconciles linkage and association studies of complex traits

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