A genome-wide association study in the Japanese population identifies the 12q24 locus for habitual coffee consumption: The J-MICC Study

Abstract

Coffee is one of the most widely consumed beverages worldwide, and its role in human health has received much attention. Although genome-wide association studies (GWASs) have investigated genetic variants associated with coffee consumption in European populations, no such study has yet been conducted in an Asian population. Here, we conducted a GWAS to identify common genetic variations that affected coffee consumption in a Japanese population of 11,261 participants recruited as a part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. Coffee consumption was collected using a self-administered questionnaire, and converted from categories to cups/day. In the discovery stage (n = 6,312), we found 2 independent loci (12q24.12-13 and 5q33.3) that met suggestive significance (P < 1 × 10^-6). In the replication stage (n = 4,949), the lead variant for the 12q24.12-13 locus (rs2074356) was significantly associated with habitual coffee consumption (P = 2.2 × 10^-6), whereas the lead variant for the 5q33.3 locus (rs1957553) was not (P = 0.53). A meta-analysis of the discovery and replication populations, and the combined analysis using all subjects, revealed that rs2074356 achieved genome-wide significance (P = 2.2 × 10^-16 for a meta-analysis). These findings indicate that the 12q24.12-13 locus is associated with coffee consumption among a Japanese population.

Figure 1

Quantile-quantile plot of genome-wide association tests using discovery samples (N = 6,312). The x-axis indicates the expected −log₁₀ P-values under the null hypothesis. The y-axis shows the observed −log₁₀ P-values calculated by a mixed linear model association method. The black line represents y = x, which corresponds to the null hypothesis. The gray shaded area shows 95% confidence intervals of the null hypothesis. The inflation factor (lambda) is the median of the observed test statistics divided by the median of the expected test statistics. Variants with P-values indicating less than suggestive significance (P < 1 × 10⁻⁶) and genome-wide significance (P < 5 × 10⁻⁸) are shown in orange and red, respectively.

Figure 2

Genome-wide association signals from the discovery samples (N = 6,312). The x-axis represents chromosomal positions and the y-axis represents −log₁₀ P-values calculated by a mixed linear model association analysis. The grey and red dotted horizontal lines indicate the suggestive (P = 1 × 10⁻⁶) and genome-wide (P = 5 × 10⁻⁸) significance levels, respectively. Variants with P-values indicating less than genome-wide significance (P < 5 × 10⁻⁸) are shown in red.

Figure 3

Association signals around the HECTD4 gene using discovery samples (N = 6,312). The x-axis represents chromosomal positions near the HECTD4 gene, and the y-axis represents −log₁₀ P-values. The top signal in this locus (rs2074356) is shown in purple. Dot color for a variant represents the degree of linkage disequilibrium (R²) estimates between each variant and rs2074356. (A) Signals from a genome-wide association scan adjusted for age and sex. (B) Signals from conditional analysis adjusted for age, sex and rs2074356 dosage.