GWAS 2.0 – Correcting for Volunteer Bias in GWAS Uncovers Novel Genetic Variants and Increases Heritability Estimates

Abstract

Selection bias in genome-wide association studies (GWASs) due to volunteer-based sampling (volunteer bias) is poorly understood. The UK Biobank (UKB), one of the largest and most widely used cohorts, is highly selected. We develop inverse probability weighted GWAS (WGWAS) to correct GWAS summary statistics in the UKB for volunteer bias. Across ten phenotypes, WGWAS decreases the effective sample size by 62% on average, compared to GWAS. WGWAS yields novel genome-wide significant associations, larger effect sizes and heritability estimates, and altered gene-set tissue expressions. The extent of volunteer bias’s impact on GWAS results varies by phenotype. Traits related to disease, health behaviors, and socioeconomic status were most affected. These findings suggest that volunteer bias in extant GWASs is substantial and call for a GWAS 2.0: a revisiting of GWAS, based on representative data sets, either through the development of inverse probability (IP) weights, or a greater focus on population-representative sampling.

Note:
Funding Information: Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health (RF1055654, R56AG058726 and R01AG078522), the Dutch National Science Foundation (016.VIDI.185.044), and the Jacobs Foundation.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: This research has been conducted using the UK Biobank Resource under Application Number 55154.