Habitual Coffee Consumption Increases Risks for Metabolic Diseases: Genome-wide Association Studies and a Phenotype-wide Two Sample Mendelian Randomization Analysis

Abstract

Abstract Background and aims: Coffee is one of the most widely consumed beverages in the world and has received considerable concerns regarding its impact on human health. Mendelian randomization (MR) could be valuable to explore the potential health effects of coffee via instrumental variables. In this study, we aim to identify novel genetic loci associated with habitual coffee consumption using genome-wide meta-analysis (GWMA) and to evaluate the broad impact of coffee consumption on human health and disease risk via a large-scale, phenotype-wide, two sample Mendelian randomization (TSMR) analysis. Methods: We conducted a genome-wide association study (GWAS) among 283,926 coffee consumers of European ancestry in the UK Biobank (UKBB) to identify single nucleotide polymorphisms (SNPs) associated with the amount of coffee consumption (cups/day, GWAS 1), caffeine intake (GWAS 2) as well as the intake of non-caffeine substance in coffee (GWAS 3). The GWAS 1 results were further combined with the published results from the Coffee and Caffeine Genetics Consortium (CCGC) for a GWMA. TSMR were performed to evaluate the causal-relationship between coffee/caffeine/non-caffeine substance consumption and 1,101 diseases and health traits. Results: The GWMA identified 50 lead SNPs among 19 genomic regions for habitual coffee consumption. Nine out of the 19 loci were novel, including ADAMTSL4-AS1, CACNA2D2, LINC02123-ADCY2, UBD-SNORD32B, SEMA4D-GADD45G, LOC101929457-LINGO1, RAI1, HCN2, and BRWD1. The GWAS 2 and 3 identified 2 (SORCS2 and SLC39A8) and 5 (LINC02060-LINC00461, AGR3-AHR, PRR4-TAS2R14, CYP1A1-CYP1A2, and FTO) genomic regions, respectively. TSMR analysis indicated that coffee consumption increased the risk of high blood lipids, obesity, and diabetes. Meanwhile, intake of caffeine and non-caffeine coffee components decreased and increased some of the blood lipids levels, respectively. Conclusions: Our study provided evidence that habitual coffee consumption could increase the risk of metabolic perturbations. The bioactive components in coffee, other than caffeine, may be more harmful to human health. Our findings have significant implications for global public health given the increasing burden of metabolic diseases.