title: A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults.
abstract: OBJECTIVE
  With rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes.
  
  
  METHODS
  We developed genetic risk scores (GRSs) from published T1D- and T2D-associated variants. We first tested whether the scores could distinguish clinically defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC) (n = 3,887). We then assessed whether the T1D GRS correctly classified young adults (diagnosed at 20-40 years of age, the age-group with the most diagnostic difficulty in clinical practice; n = 223) who progressed to severe insulin deficiency <3 years from diagnosis.
  
  
  RESULTS
  In the WTCCC, the T1D GRS, based on 30 T1D-associated risk variants, was highly discriminative of T1D and T2D (area under the curve [AUC] 0.88 [95% CI 0.87-0.89]; P < 0.0001), and the T2D GRS added little discrimination (AUC 0.89). A T1D GRS >0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (<0.234, <5th centile T1D) is indicative of T2D (53% sensitivity, 95% specificity). Most discriminative ability was obtained from just nine single nucleotide polymorphisms (AUC 0.87). In young adults with diabetes, T1D GRS alone predicted progression to insulin deficiency (AUC 0.87 [95% CI 0.82-0.92]; P < 0.0001). T1D GRS, autoantibody status, and clinical features were independent and additive predictors of severe insulin deficiency (combined AUC 0.96 [95% CI 0.94-0.99]; P < 0.0001).
  
  
  CONCLUSIONS
  A T1D GRS can accurately identify young adults with diabetes who will require insulin treatment. This will be an important addition to correctly classifying individuals with diabetes when clinical features and autoimmune markers are equivocal.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada National Institute for Health Research Exeter Clinical Research Facility, Exeter, U.K. m.n.weedon@exeter.ac.uk r.oram@exeter.ac.uk a.t.hattersley@exeter.ac.uk.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Oram
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. National Institute for Health Research Exeter Clinical Research Facility, Exeter, U.K.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, Exeter, U.K.
authors.forename: Anita
authors.initials: A
authors.lastname: Hill
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. Department of Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonald
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. National Institute for Health Research Exeter Clinical Research Facility, Exeter, U.K.
authors.forename: Angus
authors.initials: A
authors.lastname: Jones
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. National Institute for Health Research Exeter Clinical Research Facility, Exeter, U.K. m.n.weedon@exeter.ac.uk r.oram@exeter.ac.uk a.t.hattersley@exeter.ac.uk.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. m.n.weedon@exeter.ac.uk r.oram@exeter.ac.uk a.t.hattersley@exeter.ac.uk.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
mesh_terms: D000328:Adult; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000627:therapeutic use; D009765:Obesity / Q000150:complications; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors; D055815:Young Adult
chemical_list: D007328:Insulin