Effect heterogeneity reveals complex pleiotropic effects of rare coding variants

Genome-wide association studies (GWAS) and rare-variant association studies (RVAS) have identified thousands of genes and variants that affect multiple phenotypes. Here, using rare variant association results from the UK Biobank (UKB) data, we identify pervasive gene-level pleiotropy across diverse phenotypic domains and highlight genes with apparent allelic series that provide additional association support through disease pathways. We develop a statistical test, ALLSPICE, to explore allelic heterogeneity within pleiotropic genes and identify evidence for a heterogeneous effect of a subset of missense variants in the ALB gene on albumin and calcium levels, which are further validated at protein structure level. In this way, we demonstrate potential shared and trait-specific biological pathways, providing insights into the genetic basis of pleiotropy in complex human traits.