Whole Exome Sequencing Study Identifies Novel Rare Risk Variants for Habitual Coffee Consumption Involved in Olfactory Receptor and Hyperphagia

Habitual coffee consumption is an addictive behavior with unknown genetic variations and has raised public health issues about its potential health-related outcomes. We performed exome-wide association studies to identify rare risk variants contributing to habitual coffee consumption utilizing the newly released UK Biobank exome dataset (n = 200,643). A total of 34,761 qualifying variants were imported into SKAT to conduct gene-based burden and robust tests with minor allele frequency <0.01, adjusting the polygenic risk scores (PRS) of coffee intake to exclude the effect of common coffee-related polygenic risk. The gene-based burden and robust test of the exonic variants found seven exome-wide significant associations, such as OR2G2 (P(SKAT) = 1.88 × 10(−9), P(SKAT-Robust) = 2.91 × 10(−17)), VEZT1 (P(SKAT) = 3.72 × 10(−7), P(SKAT-Robust) = 1.41 × 10(−7)), and IRGC (P(SKAT) = 2.92 × 10(−5), P(SKAT-Robust) = 1.07 × 10(−7)). These candidate genes were verified in the GWAS summary data of coffee intake, such as rs12737801 (p = 0.002) in OR2G2, and rs34439296 (p = 0.008) in IRGC. This study could help to extend genetic insights into the pathogenesis of coffee addiction, and may point to molecular mechanisms underlying health effects of habitual coffee consumption.