Genome-Wide Association Studies of Coffee Intake in UK/US Participants of European Ancestry Uncover Gene-Cohort Influences

Abstract

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N=130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across thousands of biomarkers and health and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from UK Biobank (UKB; N=334,659). The results of these two GWAS were highly discrepant. We observed positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in UKB. Genetic correlations with cognition were negative in 23andMe but positive in UKB. The only consistent observations were positive genetic correlations with substance use and obesity. Our study shows that GWAS in different cohorts could capture cultural differences in the relationship between behavior and genetics.

Figure 1.. GWAS and secondary analyses of coffee intake from the 23andMe cohort.

A) Manhattan plot displays seven genome-wide significant loci for coffee intake in the 23andMe cohort (N=130,153). The horizontal line represents the threshold for significance (p=5.00E-08). Nearest protein-coding genes (<1Mb) to significant loci are labeled. Quantile-quantile plot shown in upper left corner. For more details, see Table 1 and Supplementary Table 6. B) Overlap of genes identified by MAGMA, H-MAGMA, S-PrediXcan, and S-MultiXcan. Genes identified by all four methods are displayed. C) Genes predicted to affect coffee intake identified by S-MultiXcan according to the most significantly associated biological systems. For more details, see Supplementary Table 9. D) Genes implicated in coffee intake by S-PrediXcan according to brain regions. Upregulated genes are shown in red, downregulated shown in blue. For more detail, see Supplementary Table 10.

Figure 2.. Discordant genetic and phenotypic associations with genetic disposition to coffee intake in US and UK cohorts.

A) Comparison of genetic correlations across psychiatric (light gray), anthropologic (medium gray), and health (dark gray) traits between 23andMe (lanes 1 and 2) and UKB (lanes 3 and 4). Lanes 1 and 3 show r_g values calculated by LDSC, and lanes 2 and 4 show FDR-corrected p values. Only traits for which at least one cohort was FDR-significant are displayed. For a full list of correlations and trait names, see Supplementary Table 14. Most signals persisted after conditioning for dietary sugar, cigarettes per day, and Alcohol Use Disorder Identification (AUDIT) Consumption scores using mtCOJO (Supplementary Tables 15–16; Supplementary Figures 11–12). Genetic correlations for traits denoted with * could not be calculated in both cohorts; ** denotes reverse coding. B) Phenomic associations (panel 1: PheWAS (p<3.62E-05), panel 2: LabWAS (p<1.57E-04)) identified from PGS of coffee intake from 23andMe and UKB summary statistics. Only traits for which at least one cohort was FDR-significant are displayed (saturated bars=FDR significant; desaturated bars=FDR non-significant). neuro.=neurological; gen.=genitourinary; neopl.=neoplasms; sense=sense organs; derma.=dermatologic; imm.=immune. For full trait names and more detail, see Supplementary Table 18–19.