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

Abstract

Glycated haemoglobin (HbA1c) 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 HbA1c has been estimated at ~55–75%, a much smaller proportion of phenotypic variance is explained by the HbA1c-associated variants identified so far. To search for novel loci influencing the HbA1c 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 HbA1c supported an association between the novel TMC6–TMC8 locus and HbA1c (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 HbA1c 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 HbA1c. These findings provide novel insights into the molecular mechanisms that modulate the HbA1c level in non-diabetic subjects.

A Genome-Wide Association Study Identifies the Association between the 12q24 Locus and Black Tea Consumption in Japanese Populations

“…We also excluded subjects who had inconsistent sex information between the genotype and questionnaire, who had an estimated non-Japanese ancestry, or who had a low call rate (<0.95) [ 16 , 17 ]. Furthermore, we excluded the close relationship pairs determined using the identity-by-descent method (PI_HAT > 0.1875) according to previous studies [ 8 , 13 , 18 , 19 ]. Quality control analyses were carried out using PLINK [ 20 , 21 ] (version 1.90b3.42) and Eigensoft [ 16 ] (version 6.1.3).…”

Genome-wide analysis of polymorphism × sodium interaction effect on blood pressure identifies a novel 3′-BCL11B gene desert locus

“…S7 ). Expression quantitative trait locus (eQTL) analysis using Japanese multi-omics iMETHYL datasets 25 , 32 , 33 showed that the rs8022678 A allele was weakly associated with decreased BCL11B expression level in CD4 + T cells (Supplementary Fig. S8 ).…”

“…Previous studies indicated that the 3′- BCL11B gene desert region harbours several remote enhancers that modulate BCL11B gene expression 34 , 35 . Japanese multi-omics iMETHYL datasets 25 , 32 , 33 showed that the rs8022678 A allele was weakly associated with decreased BCL11B expression level in CD4 + T cells. Some variants at the 3′- BCL11B gene desert region were associated with aortic stiffness and cardiovascular disease risk 36 , although rs8022678 was not linked with those variants by linkage disequilibrium ( r 2 = 0.002 in East Asians according to the LDlink server 37 ).…”

“…Interactions achieving suggestive significance were further examined in an independent cohort of Iwate subjects ( n = 4,241). We previously showed based on PC analysis that genetic distribution of Iwate subjects was slightly different from that of Miyagi subjects 25 . At the replication stage, P replication < 0.05 and consistent effect direction of the interaction term with the discovery cohort were considered as nominally significant.…”

“…Participants of the TMM CommCohort Study who were enrolled in 2013 were genotyped using a HumanOmniExpressExome BeadChip Array (Illumina Inc., San Diego, CA, USA) 24 , 25 . Based on the genotype data, imputation of sex information and identification of close relationship pairs were performed using PLINK software (version 1.90b3.45) 26 .…”