A genome-wide association study identifies a novel major locus for glycemic control in type 1 diabetes, as measured by both A1C and glucose

Abstract

Objective: Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.

Research design and methods: We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes.

Results: We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 x 10(-10)), which was also associated with mean glucose (P = 2 x 10(-5)). This was confirmed using A1C in the intensive treatment group (P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.

Conclusions: A major locus for A1C and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.

FIG. 1.

Association results for mean A1C levels in the conventional treatment group at a 500-kb region surrounding rs1358030 (SORCS1). On the left y-axis is the −log₁₀ (P value) for each SNP genotyped. On the right y-axis and the line is the recombination rate estimated from our data. The annotated genes in the region are indicated along the bottom of the figure. SNPs are colored based on their linkage disequilibrium with the most significant SNP, i.e., rs1358030, where black indicates the index SNP, light grey indicates 0.2 < r² < 0.5, and white indicates r² ≤ 0.2 (see the online version of the figure for colors where blue indicates the index SNP and yellow indicates 0.2 < r² < 0.5).