2008-LB: Identification of Genome-Wide Significant Loci for Childhood Glycemic Traits in HAPO Follow-up Study

Introduction & Objective: Type 2 Diabetes (T2D) among children is increasing. Compared to T1D and adult-onset T2D, it is more aggressive with more rapid disease progression. The genetic risk associated with youth-onset T2D has not been elucidated. We performed a GWAS of childhood dysglycemia and precursors to T2D in a diverse youth cohort.

Methods: The Hyperglycemia and Adverse Pregnancy Outcome Follow Up Study (HAPO FUS) cohort, a diverse cohort of children (N=4,160, ages =11-14 years) representing several ancestry groups (African=AFR, Mexican American=AMR, South Asian=SAS, European=EUR, and East Asian=EAS) was used to identify genetic variants associated with glucose dysregulation. The primary outcomes included the lowest quartile of Disposition Index (DI) and Matsuda index (MI), and highest quartile of sum of glucose Z-scores from a fasting 2-hr OGTT (2hGZ). Genome-wide SNP data were imputed to TOPMed. GWAS was performed using an additive model, adjusting for field center, 3 principal components of genetic ancestry, maternal confounders during pregnancy, and offspring confounders during childhood.

Results: We identified two genome-wide significant associations in AFR (intronic in SHOC1 and C8ORF37-AS1) and one in EAS (intergenic between GPIHBP1 and LY6H) with lowest quartile of DI. Four additional genome-wide significant associations were found in AFR (ADI1, MOK, intergenic between SLC37A3 and KDM7A-DT, and intergenic between LINC01541 and GTSCR1) for 2hGZ. One genome-wide significant locus in EAS (intronic in C2CD2) and one in EUR (intronic within INSC) were identified with MI. No associations were identified in our AMR or SAS populations.

Conclusion: Multiple loci were associated with markers of dysglycemia in ancestry-specific analyses of HAPO FUS children. While loci previously reported to be associated with glycemic measures were not identified, subsequent analyses with greater power using trans-ethnic meta-analyses will likely identify additional loci.