According to the study findings, genetic risk score (GRS), along with conventional risk factors such as body mass index (BMI) and family history of diabetes, can help identify population subgroups with very high risk of developing type 2 diabetes. The risk of developing type 2 diabetes depends on both genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in several genes have been reproducibly linked with diabetes risk at genomewide levels of significance. GRSs in the present study were based on 10 such SNPs at 9 genetic loci: HHEX, CDKAL1, IGF2BP2, SLC30A8, WFS1, CDKN2A/B, TCF7L2, PPARG, and KCNJ11. The new study evaluated whether a combination of risk variants can contribute significantly to disease risk and to prospectively identifying individuals at high risk for type 2 diabetes, although the effect of a single genetic risk variant is modest. GRSs were calculated 2 different ways: either assuming equal contribution of each risk allele or weighting the risk alleles. Participants involved were 1297 diabetic men and 1612 diabetic women, and matched men (n = 1338) and women (n = 2163) were nondiabetic control participants, all of European ancestry. DNA samples were obtained from white blood cells. Participants were assessed for BMI, family history of diabetes, current smoking, alcohol intake, physical activity, whether they were pre- or postmenopausal, and fat (polyunsaturated/saturated fatty acids ratio), trans fat, and cereal fiber intakes. In control subjects, the median count GRS was 11.0; median weighted GRS was 10.2 for women and 10.4 for men. Subjects were classified by GRS quintile, with the age- and BMI-adjusted odds ratio (OR) for the lowest quintile set to 1.00. For men, OR for type 2 diabetes risk increased across quintiles from 1.29 (95% confidence interval [CI], .97 – 1.72) in the second quintile to 2.76 (95% CI, 2.06 – 3.68) in the fifth quintile. Equivalent women's values also increased from 1.05 (95% CI, .83 – 1.34) in the second quintile to 2.17 (95% CI, 1.76 – 2.69) in the fifth quintile (trend P < .001). Each risk allele was associated with a 16% to 19% increase in the risk for type 2 diabetes. Significant (P = .023) interactions were identified between the count GRS and BMI, demonstrating a greater effect of genetic risk alleles in participants with higher BMI. The interactive effects of GRS and BMI were striking: Individuals in the fifth GRS quintile and with a BMI of 30 kg/m2 or higher had more than 14 times the risk for type 2 diabetes compared with individuals who were in the lowest GRS quintile and had a BMI lower than 25 kg/m2. The relationship between type 2 diabetes risk and family history remained even after adjusting for GRS, indicating the involvement of additional genetic loci or a stronger role for the shared family environment in the present study.