Genomic-Relatedness Matching Expands Population Coverage, Improves Power, and Reduces Bias in Genetic Association Analyses

Abstract

We introduce a novel approach, Genomic-Relatedness-Matched Association (GRMA) studies, as an alternative to genome-wide association studies (GWAS). GWAS are typically restricted to samples of mostly unrelated individuals with a single, shared continental ancestry and nevertheless can still be biased by gene-environment correlation and assortative mating. In contrast, GRMA can be implemented in ancestrally diverse samples--retaining individuals of mixed or underrepresented ancestries and eliminating the need to assign labels to ancestry groups--and can reduce bias relative to standard GWAS. GRMA matches each individual to a group of controls whose pairwise relatedness with the individual exceeds a user-specified threshold. It generates SNP-level summary statistics based on within-group associations. In applications using the UK Biobank and All of Us data, we find that GRMA compares favorably to GWAS methods in terms of bias, precision, and population coverage. GRMA enables several novel findings; for example, we find that "genetic nurture" is unlikely to be an important source of genome-wide bias in population GWAS of body mass index, height, and educational attainment. The method is computationally efficient and supported by open-source software, facilitating its application in large-scale scientific and health-related studies.