Genetics of Low Polygenic Risk Score Type 1 Diabetes Patients: rare variants in 22 novel loci

With polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included. The first cohort consisted of 3,356 T1D cases and 6,203 controls, and the independent second cohort consisted of 3,355 T1D cases and 6,203 controls. Cases with low T1D PRS were identified using PRSice-2 and compared to controls with low T1D PRS by genome-wide association (GWA) test. Twenty-six genetic loci with SNPs/SNVs associated with low PRS T1D at genome-wide significance (P[≤]5.0xE-08) were identified, including 4 established T1D loci, as well as 22 novel loci represented by rare SNVs. For the 22 novel loci, 12 regions have been reported of association with obesity related traits by previous GWA studies. Five loci encoding long intergenic non-protein coding RNAs (lncRNA), two loci involved in N-linked glycosylation, two loci encoding GTPase activators, and two ciliopathy genes, are also highlighted in this study.