A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose

A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose Andrew D. Paterson 1 , 4 , Daryl Waggott 2 , Andrew P. Boright 3 , S. Mohsen Hosseini 1 , Enqing Shen 2 , Marie-Pierre Sylvestre 2 , Isidro Wong 1 , Bhupinder Bharaj 1 , Patricia A. Cleary 5 , John M. Lachin 5 , MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) * , Jennifer E. Below 8 , Dan Nicolae 8 , Nancy J. Cox 8 , Angelo J. Canty 6 , Lei Sun 4 , 7 , Shelley B. Bull 2 , 4 and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group † 1 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada; 2 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada; 3 Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; 4 Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; 5 The Biostatistics Center, The George Washington University, Rockville, Maryland; 6 Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada; 7 Department of Statistics, University of Toronto, Canada; 8 Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois. Corresponding author: Andrew Paterson, andrew.paterson{at}utoronto.ca . 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 × 10 −10 ), which was also associated with mean glucose ( P = 2 × 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. Footnotes *A complete list of investigators of MAGIC is provided in online appendix supplementary Table 10, available at https://diabetesjournals.org/diabetes/article/59/2/539/24794/A-Genome-Wide-Association-Study-Identifies-a-Novel . †A complete list of investigators and members of the research group appears in N Engl J Med 2005;353:2643–2653. Clinical trial registry nos. NCT00360815 (DCCT) and NCT00360893 (EDIC), clinicaltrials.gov . The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 332 . . Received May 1, 2009. Accepted October 20, 2009. © 2010 by the American Diabetes Association.