Genetic architecture reconciles linkage and association studies of complex traits

doi:10.1038/s41588-024-01940-2

. 2024 Nov;56(11):2352-2360.

doi: 10.1038/s41588-024-01940-2. Epub 2024 Oct 7.

Genetic architecture reconciles linkage and association studies of complex traits

Julia Sidorenko¹, Baptiste Couvy-Duchesne^{2

3

4}, Kathryn E Kemper², Gunn-Helen Moen^{2

5

6

7}, Laxmi Bhatta⁶, Bjørn Olav Åsvold^{6

8

9}, Reedik Mägi¹⁰; Estonian Biobank Research Team; Alireza Ani^{11

12}, Rujia Wang¹¹, Ilja M Nolte¹⁰; Lifelines Cohort Study; Scott Gordon³, Caroline Hayward¹³, Archie Campbell¹⁴, Daniel J Benjamin^{15

16

17}, David Cesarini^{17

18

19}, David M Evans^{2

7

20}, Michael E Goddard^{21

22}, Chris S Haley^{23

24

25}, David Porteous¹³, Sarah E Medland³, Nicholas G Martin³, Harold Snieder¹¹, Andres Metspalu¹⁰, Kristian Hveem^{6

8}, Ben Brumpton^{6

8}, Peter M Visscher^{26

27}, Loic Yengo²⁸

Collaborators, Affiliations

Collaborator

Ilja M Nolte

Affiliations

¹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. j.sidorenko@imb.uq.edu.au.
² Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴ Sorbonne University, Paris Brain Institute-ICM, CNRS, INRIA, INSERM, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France.
⁵ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁶ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia.
⁸ HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
⁹ Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway.
¹⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
¹¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹² Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
¹³ MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁵ Human Genetics Department, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁶ Behavioral Decision Making Group, Anderson School of Management, University of California Los Angeles, Los Angeles, CA, USA.
¹⁷ National Bureau of Economic Research, Cambridge, MA, USA.
¹⁸ Department of Economics, New York University, New York, NY, USA.
¹⁹ Center for Experimental Social Science, New York University, New York, NY, USA.
²⁰ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
²¹ Centre for AgriBioscience, Agriculture Victoria, Bundoora, Victoria, Australia.
²² Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.
²³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²⁴ Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK.
²⁵ Coupland Craft Cider, Coupland, Northumberland, UK.
²⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
²⁷ 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.
²⁸ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. l.yengo@imb.uq.edu.au.

PMID: 39375568
DOI: 10.1038/s41588-024-01940-2

Genetic architecture reconciles linkage and association studies of complex traits

Julia Sidorenko et al. Nat Genet. 2024 Nov.

. 2024 Nov;56(11):2352-2360.

doi: 10.1038/s41588-024-01940-2. Epub 2024 Oct 7.

Authors

Collaborator

Ilja M Nolte

Affiliations

¹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. j.sidorenko@imb.uq.edu.au.
² Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴ Sorbonne University, Paris Brain Institute-ICM, CNRS, INRIA, INSERM, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France.
⁵ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁶ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia.
⁸ HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
⁹ Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway.
¹⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
¹¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹² Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
¹³ MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁵ Human Genetics Department, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁶ Behavioral Decision Making Group, Anderson School of Management, University of California Los Angeles, Los Angeles, CA, USA.
¹⁷ National Bureau of Economic Research, Cambridge, MA, USA.
¹⁸ Department of Economics, New York University, New York, NY, USA.
¹⁹ Center for Experimental Social Science, New York University, New York, NY, USA.
²⁰ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
²¹ Centre for AgriBioscience, Agriculture Victoria, Bundoora, Victoria, Australia.
²² Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.
²³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²⁴ Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK.
²⁵ Coupland Craft Cider, Coupland, Northumberland, UK.
²⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
²⁷ 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.
²⁸ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. l.yengo@imb.uq.edu.au.

PMID: 39375568
DOI: 10.1038/s41588-024-01940-2

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.

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References

1. Polderman, T. J. C. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47, 702–709 (2015). - PubMed - DOI
1. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996). - PubMed - DOI
1. Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, Inc., 1998).
1. Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33, 228–237 (2003). - PubMed - DOI
1. Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990). - PubMed - DOI

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[1] Polderman, T. J. C. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47, 702–709 (2015). - PubMed - DOI

[2] Polderman, T. J. C. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47, 702–709 (2015). - PubMed - DOI

[3] Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996). - PubMed - DOI

[4] Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996). - PubMed - DOI

[5] Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, Inc., 1998).

[6] Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, Inc., 1998).

[7] Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33, 228–237 (2003). - PubMed - DOI

[8] Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33, 228–237 (2003). - PubMed - DOI

[9] Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990). - PubMed - DOI

[10] Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990). - PubMed - DOI

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Genetic architecture reconciles linkage and association studies of complex traits

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Genetic architecture reconciles linkage and association studies of complex traits

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