Sixty-five common genetic variants and prediction of type 2 diabetes

Philippa J Talmud, Jackie A Cooper, Richard W Morris, Frank Dudbridge, Tina Shah, Jorgen Engmann, Caroline Dale, Jon White, Stela McLachlan, Delilah Zabaneh, Andrew Wong, Ken K Ong, Tom Gaunt, Michael V Holmes, Debbie A Lawlor, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Claudia LangenbergYoav Ben-Shlomo, S Goya Wannamethee, Mark Wj Strachan, Meena Kumari, John C Whittaker, Fotios Drenos, Mika Kivimaki, Aroon D Hingorani, Jacqueline F Price, Steve E Humphries, UCLEB Consortium

Research output: Contribution to journalArticle (Academic Journal)peer-review

77 Citations (Scopus)


We developed a 65-T2D variant weighted gene score to examine the impact on T2D risk assessment in a UK-based consortium of prospective studies, initially free from type 2 diabetes (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 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 scores Net Reclassification Improvement (NRI) was 8.1% (5.0 to 11.2) p=3.31x10(-7). While BMI stratification into tertiles influenced the NRI (95% CI) (BMI<24.5kg/m(2) (27.6% (17.7 to 37.5) p=4.82x10(-8)); 24.5-27.5kg/m(2) (11.6% (5.8 to 17.4) p=9.88x10(-5)); >27.5kg/m(2) (2.6% (-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.

Original languageEnglish
JournalDiabetic Medicine
Publication statusPublished - 4 Dec 2014

Bibliographical note

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.


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