Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations

Abstract

Abstract GWAS have generally focused on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we use whole-genome sequencing data to evaluate the contribution to and architecture of rare non-coding variants for three commonly studied anthropometric traits: height, BMI and waist-hip ratio adjusted for BMI. Analysing 447,461 individuals in the UK Biobank for discovery and 225,515 individuals in All of Us for replication, we identify 90 rare and low-frequency single variant associations, including two independent rare variants upstream of IGF2BP2 that substantially reduce waist-hip ratio adjusted for BMI, but have distinct effects on other adiposity traits. We further identify 135 coding variant aggregates. For example, UBR3 protein-truncating variants are associated with a 2.7 kg/m2 increase in BMI. We additionally identify 51 non-coding variant aggregate associations, including one in the 5’UTR of FGF18 associated with up to 6 cm effects on height. We show that 97% of rare variant associations occur near GWAS-identified loci, demonstrating convergence of rare and common variant associations. Finally, we show that ultra rare variants explain a small fraction of heritability compared to common variants for these traits, that heritability is largely shared across ancestries, and that it concentrates around common variant loci.