Genome-Wide Significant Genes Identified for Youth-Onset Type 2 Diabetes

The first genome-wide association study (GWAS) for youth-onset type 2 diabetes (T2D) identified known and novel risk loci, and the study results were published in Diabetes.

The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium combined data from 3 studies (TODAY, T2D-GENES, and SEARCH) for a total of 3006 youth with T2D, 6061 adult controls, and 856 youth controls. Variants were obtained by using the Infinium GWAS array, genotypes were called using the Autocall algorithm, and missing data were imputed in PLINK2 using 1000 Genomes Phase 3 v5 data. Significant variants were identified using a generalized linear mixed model.

Demographics for each group (youth with T2D, adult participants, and youth controls) were as follows: 62%, 57%, and 52% were women and girls; 22%, 24%, and 63 were White; 36%, 18%, and 37% were Black; and 42%, 59%, and 0% were Hispanic, respectively.

The GWAS identified, at genome-wide significance, variants in 6 genes that had previously been associated with T2D (transcription factor 7 like 2 [TCF7L2], melanocortin 4 receptor [MC4R], cell division cycle 123 [CDC123], potassium voltage-gated channel subfamily Q member 1 [KCNQ1], insulin-like growth factor 2 MRNA binding protein 2 [IGF2BP2], solute carrier family 16 member 11 [SLC16A11]), and in 1 novel gene (PHD finger protein 2 [PHF2]).

Fine mapping of the region of the novel gene identified 38 possible causal variants. Comparing the youth with T2D with controls and correcting for body mass index (BMI) identified rs2604566 in the gene cytoplasmic polyadenylation element binding protein 2 (CPEB2; odds ratio [OR], 2.1; P =3.2 x 10^-8), which was previously associated with T2D among adults (OR, 1.11; P =.014).

With data from previously published variants associated with T2D among adults, the investigators found directional replication for 86% of their variants at a significance of P <2.2 x 10^-16 comparing youth with T2D with adult controls and 71% of the variants at a significance of P <1.3 x 10^-13 comparing youth with T2D with youth controls.

Polygenic risk for youth-onset T2D was highest among Hispanic individuals (OR, 2.49; 95% CI, 2.28-2.72; P <2 x 10^-16) followed by White individuals (OR, 2.44; 95% CI, 2.17-2.75; P =2 x 10^-16) and Black individuals (OR, 1.45; 95% CI, 1.32-1.60; P =3.7 x 10^-15).

The investigators report that this was the first GWAS to associate genetic variants with youth-onset T2D by identifying a total of 7 genome-wide significant genes.

Reference

Srinivasan S, Chen L, Todd J, et al; on behalf of the ProDiGY Consortium. The first genome-wide association study for type 2 diabetes in youth: the Progress in Diabetes Genetics in Youth (ProDiGY) Consortium. Diabetes. 2021;70(4):996-1005. doi:10.2337/db20-0443