A genome-wide association study and genetic risk score for age at diabetes diagnosis support beta-cell dysfunction in young-onset diabetes in Chinese

Background We investigated genetic variations driving young age-at-diabetes-diagnosis (ADD) and developed a genetic risk score (GRS) to identify Chinese individuals at risk of young-onset diabetes (YOD with ADD<40). Methods We performed genome-wide association studies (GWAS) for ADD with internal and external replication in 22,611 individuals with type 2 diabetes (T2D, 20% with YOD) and identified Chinese-prioritized loci by conditioning on the polygenic risk score (PRS) of ADD constructed from publicly available datasets. We constructed ADD-GRS using genome-wide independent variants (p<5E-08) and examined its associations with glycemic traits in diabetes and non-diabetes cohorts. Results We identified three independent signals at genome-wide significance ( P < 5×10−8) mapping to CDKAL1 (rs2206734, β=-0.75 (SE:0.13) per copy of T allele, effect allele frequency (EAF)=0.38, p =2.12E-09), PAX4 (rs61160304, β=-1.01 (SE:0.17) per copy of T allele, EAF=0.19, p =2.51E-09), and KCNQ1 (rs2299620, β=-0.77 (SE:0.14) per copy of G allele, EAF=0.70, p=2.80E-08). The variants at PAX4 and KCNQ1 were independent of the genetic liability estimated by ADD-PRS from Europeans and South Indians. In the diabetes cohort, the ADD-GRS was associated with younger ADD, lower C-peptide, higher HbA1c and pathway-specific T2D-PRS for beta-cell+proinsulin and residual glycemia. Using YOD versus later-onset diabetes as a secondary outcome, LINC02783/PADI1 (rs72895704, OR:1.52 per copy of A allele, EAF=0.02, p =1.93E-06) and TARS2P1 (rs145218437, OR: 1.73 per copy of C allele, EAF=0.02, p =7.57E-08) showed suggestive significance. Conclusions Both known and novel T2D loci contribute to ADD in Chinese people and may be used to detect high risk individuals for early intervention to prevent or delay onset of YOD.