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Background: A bidirectional relationship between chronic pain (CP) and mental disorders has been reported, and coffee was believed to be associated with both. However, the association of coffee in this bidirectional relationship remains unclear. We aim to analyze the association of coffee consumption on the relationship of CP with depression and anxiety., Methods: A total of 376,813 participants from UK Biobank were included. We collected data on anxiety, depression and CP from objects of our study population. The association of coffee consumption on the relationship of CP with depression and anxiety was assessed through logistic/linear regression models. Moreover, seemingly unrelated estimation test (SUEST) was used to compare whether the coefficients differed in two different groups., Results: We observed significant associations of coffee consumption in the interaction of CP with depression and anxiety, such as the association of multisite chronic pain (MCP) on self-reported depression ( β coffee  = 0.421, β non-coffee  = 0.488, P SUEST   = 0.001), and the association of MCP on generalized anxiety disorder-7 (GAD-7) scores ( β coffee  = 0.561, β non-coffee  = 0.678, P SUEST   = 0.004) were significantly different between coffee drinking and non-coffee drinking groups. Furthermore, in analysis stratified by gender, we found headache ( β male  = 0.392, β female  = 0.214, P SUEST   = 0.022) and hip pain ( β male  = 0.480, β female  = 0.191, P SUEST   = 0.021) had significant associations with self-reported depression between males and females groups in coffee drinkers., Conclusions: Our results suggested that coffee consumption has a significant association on the relationship of CP with depression and anxiety.

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 (PSKAT = 1.88 × 10−9, PSKAT-Robust = 2.91 × 10−17), VEZT1 (PSKAT = 3.72 × 10−7, PSKAT-Robust = 1.41 × 10−7), and IRGC (PSKAT = 2.92 × 10−5, PSKAT-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.