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

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.