Phenome-wide association study of population-differentiating genetic variants around gene .

BACKGROUND AND OBJECTIVES

Demographic dynamics and natural selection during human evolution shaped the present-day patterns of genetic variations, and geographically varying genetic factors contribute to different disease prevalences across human populations. This study aims to evaluate the presence of positive selection on the gene encoding long-chain fatty acyl-CoA synthetase 1 () and the phenotypic impacts of population-differentiating genetic variants around this gene.

METHODOLOGY

Three types of statistical tests for positive selection, based on site frequency spectrum, extended haplotype homozygosity and population differentiation, were applied to the whole-genome sequencing data from the 1000 Genomes Project. A phenome-wide association study of was performed with published genome-wide association studies (GWAS) and transcriptome-wide association studies, including phenome-wide studies in biobanks.

RESULTS

Genetic variants associated with expression in various tissues exhibit geographically varying allele frequencies. Three types of statistical tests consistently supported the presence of positive selection on the coding and regulatory regions of in African, European, South Asian and East Asian populations. A phenome-wide association study of revealed associations with type 2 diabetes, blood glucose, age at menopause, mean platelet volume and mean reticulocyte volume. The top allele associated with lower diabetes risk has the highest frequency in European populations, whereas the top allele associated with later menopause has the highest frequency in African populations.

CONCLUSIONS AND IMPLICATIONS

Positive selection on resulted in geographically varying genetic variants, which may contribute to differential phenotypes across human populations, including type 2 diabetes and age at menopause.