title: 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.
  
  
  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.
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada. andrew.paterson@utoronto.ca
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Boright
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.forename: Enqing
authors.initials: E
authors.lastname: Shen
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Sylvestre
authors.forename: Isidro
authors.initials: I
authors.lastname: Wong
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Bharaj
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cleary
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.forename: Dan
authors.initials: D
authors.lastname: Nicolae
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Canty
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Bull
mesh_terms: D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D048909:Diabetes Complications / Q000453:epidemiology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D004334:Drug Administration Schedule; D005006:Ethnicity; D055106:Genome-Wide Association Study / Q000379:methods*; D006442:Glycated Hemoglobin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D015201:Meta-Analysis as Topic; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups; D011956:Receptors, Cell Surface / Q000235:genetics; D012016:Reference Values; D035781:Siblings
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D011956:Receptors, Cell Surface; C472780:SORCS1 protein, human