Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA1c

Glycated haemoglobin (HbA_1c) is widely used as a biomarker for the diagnosis of diabetes, for population-level screening, and for monitoring the glycaemic status during medical treatment. Although the heritability of HbA_1c has been estimated at ~55-75%, a much smaller proportion of phenotypic variance is explained by the HbA_1c-associated variants identified so far. To search for novel loci influencing the HbA_1c levels, we conducted a genome-wide meta-analysis of 2 non-diabetic Japanese populations (n = 7,704 subjects in total). We identified 2 novel loci that achieved genome-wide significance: TMC6-TMC8 (P = 5.3 × 10^-20) and SIX3-SIX2 (P = 8.6 × 10^-9). Data from the largest-scale European GWAS conducted for HbA_1c supported an association between the novel TMC6-TMC8 locus and HbA_1c (P = 2.7 × 10^-3). The association analysis with glycated albumin and glycation gap conducted using our Japanese population indicated that the TMC6-TMC8 and SIX3-SIX2 loci may influence the HbA_1c level through non-glycaemic and glycaemic pathways, respectively. In addition, the pathway-based analysis suggested that the linoleic acid metabolic and 14-3-3-mediated signalling pathways were associated with HbA_1c. These findings provide novel insights into the molecular mechanisms that modulate the HbA_1c level in non-diabetic subjects.