Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection

TLDR

GWAS may have reached their limit in detecting common T2D‑associated genetic variation, suggesting that further optimization of polygenic prediction will require novel analytic methods and inclusion of less common or functional variants. The study evaluated whether a 62‑locus genotype risk score, separate β‑cell and insulin‑resistance scores, and their relationships across blacks and whites improve polygenic T2D prediction. The authors used data from 1,650 white and 820 black CARDIA participants and 3,471 white FOS participants, following them for 25 years to assess T2D incidence. The 62‑locus GRSt was significantly associated with incident T2D in all groups, improved the C statistic in FOS but not CARDIA, and did not materially improve risk reclassification; GRSβ predicted incident T2D among whites but not GRSIR, and overall polygenic scores predict T2D in whites and blacks but do not outperform clinical models.

Abstract

Genome-wide association studies (GWAS) may have reached their limit of detecting common type 2 diabetes (T2D)–associated genetic variation. We evaluated the performance of current polygenic T2D prediction. Using data from the Framingham Offspring (FOS) and the Coronary Artery Risk Development in Young Adults (CARDIA) studies, we tested three hypotheses: 1) a 62-locus genotype risk score (GRSt) improves T2D prediction compared with previous less inclusive GRSt; 2) separate GRS for β-cell (GRSβ) and insulin resistance (GRSIR) independently predict T2D; and 3) the relationships between T2D and GRSt, GRSβ, or GRSIR do not differ between blacks and whites. Among 1,650 young white adults in CARDIA, 820 young black adults in CARDIA, and 3,471 white middle-aged adults in FOS, cumulative T2D incidence was 5.9%, 14.4%, and 12.9%, respectively, over 25 years. The 62-locus GRSt was significantly associated with incident T2D in all three groups. In FOS but not CARDIA, the 62-locus GRSt improved the model C statistic (0.698 and 0.726 for models without and with GRSt, respectively; P < 0.001) but did not materially improve risk reclassification in either study. Results were similar among blacks compared with whites. The GRSβ but not GRSIR predicted incident T2D among FOS and CARDIA whites. At the end of the era of common variant discovery for T2D, polygenic scores can predict T2D in whites and blacks but do not outperform clinical models. Further optimization of polygenic prediction may require novel analytic methods, including less common as well as functional variants.