Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk

Abstract

Objectives: Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes (T2D). A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here we assess the ability of 18 confirmed T2D variants to differentiate between T2D cases and controls.

Research design and methods: We assessed index SNPs for the 18 independent loci in 2598 controls and 2309 cases from the GoDARTS study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of T2D, and by calculating the area-under the receiver-operator characteristic curve (AUC).

Results: Individuals carrying more risk alleles had higher risk of T2D. For example, 1.2% of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI: 2.11, 8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI and gender was 0.78, and adding the genetic risk variants only marginally increased this to 0.80.

Conclusions: Currently, common risk variants for T2D do not provide strong predictive value at a population level. However, the joint effect of risk variants identified sub-groups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing.