Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians

Abstract

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

Figure 1

Manhattan plot of genome-wide meta-analysis of stage 1 cohorts. The −log₁₀ of the association P values (y-axis) are plotted against the genomic coordinates (x-axis). The horizontal line in the plot indicates the genome-wide significance (5 × 10⁻⁸). The most relevant gene of each signal was labeled on the top of it, with the novel loci presented in brown and known loci in blue.

Figure 2

The bivariate plot of the effect directions in our meta-analysis and in previous reports. For the index SNPs in the previous GWAS, we plotted the reported effect (x-axis) versus the AGEN effect (y-axis). Whenever available, we used the effects reported by Soranzo et al. (3). The solid dots represent the SNPs that were significant (P value ≤0.05) in our study, while the hollow red dots represent the insignificant ones. The CDKAL1 top SNP reported in Koreans was specially marked by a diamond. EA, East Asian.

Figure 3

Regional association plots of the novel loci. The −log₁₀ of association P values are plotted against the genomic coordinates. The index SNPs are indicated in purple, with circles for stage 1 and squares for stage 1+2. Other SNPs are colored from red to blue as per their LD with the index SNP. Chr, chromosome.