UGI External Seminar - Dr Dora Koller - Yale School of Medicine

Abstract :  Evidence of how human evolution shaped the polygenicity of human traits and diseases has been extensively studied in populations of European descent. However, limited information is currently available about its impact on other ancestry groups. Here, we investigated how different evolutionary processes affected the common variant heritability of traits and diseases in East Asian (EAS) and European (EUR) populations. Leveraging genome-wide association statistics from the Biobank Japan (158,284 EAS participants) and UK Biobank (420,531 EUR participants), we assessed natural selection (negative and positive), archaic introgression from Neanderthal and Denisova, and several genomic functional categories with respect to the heritability of physiological and pathological conditions. In both EAS and EUR, the heritability estimates for the traits tested were enriched for negative selection annotations (false discovery rate, FDR q<0.05). In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). We followed up these enrichments by conducting a phenome-wide association study (PheWAS) of Denisovan and Neanderthal alleles in participants of six ancestral backgrounds from the UK Biobank. In EAS, Denisovan-inherited alleles were associated with 22 phenotypes, including metabolic, immunological, cardiovascular, endocrine, and dermatological traits. The strongest association was observed for the Denisovan-inherited locus rs59185462 with rheumatoid arthritis (beta=0.82, p=1.91×10^-105). In summary, our study provides the first evidence regarding the impact of evolutionary processes on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.