Insights from complex trait fine-mapping across diverse populations

Abstract

Despite the great success of genome-wide association studies (GWAS) in identifying genetic loci significantly associated with diseases, the vast majority of causal variants underlying disease-associated loci have not been identified1-3. To create an atlas of causal variants, we performed and integrated fine-mapping across 148 complex traits in three large-scale biobanks (BioBank Japan4,5, FinnGen6, and UK Biobank7,8; total n = 811,261), resulting in 4,518 variant-trait pairs with high posterior probability (> 0.9) of causality. Of these, we found 285 high-confidence variant-trait pairs replicated across multiple populations, and we characterized multiple contributors to the surprising lack of overlap among fine-mapping results from different biobanks. By studying the bottlenecked Finnish and Japanese populations, we identified 21 and 26 putative causal coding variants with extreme allele frequency enrichment (> 10-fold) in these two populations, respectively. Aggregating data across populations enabled identification of 1,492 unique fine-mapped coding variants and 176 genes in which multiple independent coding variants influence the same trait (i.e., with an allelic series of coding variants). Our results demonstrate that fine-mapping in diverse populations enables novel insights into the biology of complex traits by pinpointing high-confidence causal variants for further characterization.