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Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits Publisher Pubmed



Sidorenko J1 ; Couvyduchesne B1, 2, 3 ; Kemper KE1 ; Moen GH1, 4, 5, 6 ; Bhatta L5 ; Asvold BO5, 7, 8 ; Magi R9 ; Ani A10, 11 ; Wang R10 ; Nolte IM9, 10 ; Gordon S2 ; Hayward C12 ; Campbell A14 ; Benjamin DJ16, 17, 18 Show All Authors
Authors
  1. Sidorenko J1
  2. Couvyduchesne B1, 2, 3
  3. Kemper KE1
  4. Moen GH1, 4, 5, 6
  5. Bhatta L5
  6. Asvold BO5, 7, 8
  7. Magi R9
  8. Ani A10, 11
  9. Wang R10
  10. Nolte IM9, 10
  11. Gordon S2
  12. Hayward C12
  13. Campbell A14
  14. Benjamin DJ16, 17, 18
  15. Cesarini D18, 19, 20
  16. Evans DM1, 6, 21
  17. Goddard ME22, 23
  18. Haley CS24, 25, 26
  19. Porteous D12
  20. Medland SE2
  21. Martin NG2
  22. Snieder H10
  23. Metspalu A9
  24. Hveem K5, 7
  25. Brumpton B5, 7
  26. Visscher PM1, 27
  27. Yengo L1

Source: Nature Genetics Published:2024


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