title: Sixty-five common genetic variants and prediction of type 2 diabetes.
abstract: We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K. p.talmud@ucl.ac.uk.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K.
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: Department of Primary Care and Population Health, University College London, Royal Free Campus, London, U.K.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Morris
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, U.K.
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K.
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K.
authors.forename: Jorgen
authors.initials: J
authors.lastname: Engmann
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, U.K.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dale
authors.affiliation: University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, U.K.
authors.forename: Jon
authors.initials: J
authors.lastname: White
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, U.K.
authors.forename: Stela
authors.initials: S
authors.lastname: McLachlan
authors.affiliation: University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, U.K.
authors.forename: Delilah
authors.initials: D
authors.lastname: Zabaneh
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, U.K. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K. Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, U.K. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K.
authors.forename: Marcus
authors.initials: M
authors.lastname: Richards
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hardy
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuh
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wareham
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: Department of Primary Care and Population Health, University College London, Royal Free Campus, London, U.K.
authors.forename: S Goya
authors.initials: SG
authors.lastname: Wannamethee
authors.affiliation: Metabolic Unit, Western General Hospital, Edinburgh, U.K.
authors.forename: Mark W J
authors.initials: MW
authors.lastname: Strachan
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K.
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.affiliation: Genetics Division, Research and Development, GlaxoSmithKline, Harlow, U.K.
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.affiliation: Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K. Centre for Clinical Pharmacology, University College London, London, U.K.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, U.K.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Price
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012307:Risk Factors; D012737:Sex Factors