Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Social Science Genetic Association Consortium, Within Family Consortium

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Original languageEnglish (US)
Pages (from-to)581-592
Number of pages12
JournalNature Genetics
Volume54
Issue number5
DOIs
StatePublished - May 1 2022

Bibliographical note

Funding Information:
L.J.H., T.T.M., Y.C., D.A.L., G.D.S., G.H. and N.M.D. work in a unit that receives support from the University of Bristol and the UK MRC (grant nos. MC_UU_00011/1 & 6). N.M.D. is supported by a Norwegian Research Council Grant (no. 295989). G.H. is supported by the Wellcome Trust and Royal Society (grant no. 208806/Z/17/Z). B.M.B., B.O.Å., H.R., A.F.H. and K.H. work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen, the Liaison Committee for education, research and innovation in Central Norway and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. Funding information for other co-authors is contained in the Supplementary information. We thank H. Mostafavi and J. Pritchard for helpful suggestions and guidance relating to the polygenic adaptation analyses.

Funding Information:
L.J.H., T.T.M., Y.C., D.A.L., G.D.S., G.H. and N.M.D. work in a unit that receives support from the University of Bristol and the UK MRC (grant nos. MC_UU_00011/1 & 6). N.M.D. is supported by a Norwegian Research Council Grant (no. 295989). G.H. is supported by the Wellcome Trust and Royal Society (grant no. 208806/Z/17/Z). B.M.B., B.O.Å., H.R., A.F.H. and K.H. work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen, the Liaison Committee for education, research and innovation in Central Norway and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. Funding information for other co-authors is contained in the . We thank H. Mostafavi and J. Pritchard for helpful suggestions and guidance relating to the polygenic adaptation analyses.

Publisher Copyright:
© 2022, The Author(s).

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