Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits

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

Sidorenko J¹ ; Couvyduchesne B^{1, 2, 3} ; Kemper KE¹ ; Moen GH^{1, 4, 5, 6} ; Bhatta L⁵ ; Asvold BO^{5, 7, 8} ; Magi R⁹ ; Ani A^{10, 11} ; Wang R¹⁰ ; Nolte IM^{9, 10} ; Gordon S² ; Hayward C¹² ; Campbell A¹⁴ ; Benjamin DJ^{16, 17, 18} Show All Authors

Sidorenko J¹
Couvyduchesne B^{1, 2, 3}
Kemper KE¹
Moen GH^{1, 4, 5, 6}
Bhatta L⁵
Asvold BO^{5, 7, 8}
Magi R⁹
Ani A^{10, 11}
Wang R¹⁰
Nolte IM^{9, 10}
Gordon S²
Hayward C¹²
Campbell A¹⁴
Benjamin DJ^{16, 17, 18}
Cesarini D^{18, 19, 20}
Evans DM^{1, 6, 21}
Goddard ME^{22, 23}
Haley CS^{24, 25, 26}
Porteous D¹²
Medland SE²
Martin NG²
Snieder H¹⁰
Metspalu A⁹
Hveem K^{5, 7}
Brumpton B^{5, 7}
Visscher PM^{1, 27}
Yengo L¹

Show Affiliations

1. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
2. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
3. Sorbonne University, Paris Brain Institute—ICM, CNRS, INRIA, INSERM, AP-HP, Hopital de la Pitie Salpetriere, Paris, France
4. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
5. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
6. The Frazer Institute, University of Queensland, Woolloongabba, QLD, Australia
7. HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
8. Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway
9. Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
10. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
11. Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
12. MRC Human Genetics Unit, Institute of Genetics & amp
13. Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
14. Centre for Genomic and Experimental Medicine, Institute of Genetics & amp
15. Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
16. Human Genetics Department, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
17. Behavioral Decision Making Group, Anderson School of Management, University of California Los Angeles, Los Angeles, CA, United States
18. National Bureau of Economic Research, Cambridge, MA, United States
19. Department of Economics, New York University, New York, NY, United States
20. Center for Experimental Social Science, New York University, New York, NY, United States
21. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
22. Centre for AgriBioscience, Agriculture Victoria, Bundoora, VIC, Australia
23. Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC, Australia
24. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
25. Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, United Kingdom
26. Coupland Craft Cider, Coupland, Northumberland, United Kingdom
27. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom

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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Style	Citing Format
MLA	Sidorenko J, et al.. "Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits." Nature Genetics, vol. 56, no. 11, 2024, pp. 2352-2360.
APA	Sidorenko J, Couvyduchesne B, Kemper KE, Moen GH, Bhatta L, Asvold BO, Magi 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, ... Yengo L (2024). Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits. Nature Genetics, 56(11), 2352-2360.
Chicago	Sidorenko J, Couvyduchesne B, Kemper KE, Moen GH, Bhatta L, Asvold BO, Magi R, et al.. "Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits." Nature Genetics 56, no. 11 (2024): 2352-2360.
Harvard	Sidorenko J et al. (2024) 'Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits', Nature Genetics, 56(11), pp. 2352-2360.
Vancouver	Sidorenko J, Couvyduchesne B, Kemper KE, Moen GH, Bhatta L, Asvold BO, et al.. Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits. Nature Genetics. 2024;56(11):2352-2360.
BibTex	@article{ author = {Sidorenko J and Couvyduchesne B and Kemper KE and Moen GH and Bhatta L and Asvold BO and Magi R and Ani A and Wang R and Nolte IM and Gordon S and Hayward C and Campbell A and Benjamin DJ and Cesarini D and Evans DM and Goddard ME and Haley CS and Porteous D and Medland SE and Martin NG and Snieder H and Metspalu A and Hveem K and Brumpton B and Visscher PM and Yengo L}, title = {Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits}, journal = {Nature Genetics}, volume = {56}, number = {11}, pages = {2352-2360}, year = {2024} }
RIS	TY - JOUR AU - Sidorenko J AU - Couvyduchesne B AU - Kemper KE AU - Moen GH AU - Bhatta L AU - Asvold BO AU - Magi R AU - Ani A AU - Wang R AU - Nolte IM AU - Gordon S AU - Hayward C AU - Campbell A AU - Benjamin DJ AU - Cesarini D AU - Evans DM AU - Goddard ME AU - Haley CS AU - Porteous D AU - Medland SE AU - Martin NG AU - Snieder H AU - Metspalu A AU - Hveem K AU - Brumpton B AU - Visscher PM AU - Yengo L TI - Genetic Architecture Reconciles Linkage and Association Studies of Complex Traits JO - Nature Genetics VL - 56 IS - 11 SP - 2352 EP - 2360 PY - 2024 ER -

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