Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients

Jingchun Qu,Hakon Hakonarson,Xiao Chang,Hui-Qi Qu,Jonathan P Bradfield,Michael March,Joseph T Glessner,Lifeng Tian,Jeffrey D Roizen,Patrick M A Sleiman,John J Connolly

doi:10.1038/s41598-021-94994-9

Abstract

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 3302 T1D cases and 6181 controls, and the independent second cohort consisted of 3297 T1D cases and 6169 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. Thirteen novel genetic loci with high imputation quality (Quality Score r2 > 0.91) were identified of SNPs/SNVs associated with low PRS T1D at genome-wide significance (P ≤ 5.0 × E−08), in addition to 4 established T1D loci, 3 reported loci by our previous study, as well as 9 potential novel loci represented by rare SNVs, but with relatively low imputation quality (Quality Score r2 < 0.90). For the 13 novel loci, 9 regions have been reported of association with obesity related traits by previous GWA studies. Three loci encoding long intergenic non-protein coding RNAs (lncRNA), and 2 loci involved in N-linked glycosylation are also highlighted in this study.

Highlights

Type 1 diabetes (T1D) is caused by T-cell mediated autoimmune destruction of pancreatic β-cells[1]
The low polygenic risk score (PRS) cases may include maturity-onset diabetes of the young (MODY) patients, there are no MODY mutation identified with genome-wide significance in this GWAS study, which is as expected while generation sequencing, e.g. whole exome sequencing, is the more proper approach
Based on the single nucleotide polymorphisms (SNP) markers with T1D association P value ≤ 1E−05, a PRS score was acquired for each individual in the independent test cohort

Summary

Introduction

Type 1 diabetes (T1D) is caused by T-cell mediated autoimmune destruction of pancreatic β-cells[1]. With the rapid advances in human genomics technology in recent years, over 70 T1D loci have been identified[8] (https://www.ebi.ac.uk/gwas/) While these discoveries of T1D-associated genes have greatly increased our knowledge of T1D, our current genetic knowledge on T1D is far from complete, and a large number of T1D genes remain u ncovered[9]. The T1D loci identified by the GWAS studies to date are mainly associated with the genetic susceptibility of the major component of the heterogeneous T1D phenotype, i.e. T1aD, while the genetic susceptibility of the minor non-autoimmune components (e.g. T1bD and misdiagnosed MODY) are under-represented in those results likely as a result of being diluted. Our aim in this study is to identify low PRS T1D cases and to run a separate GWAS in an attempt to uncover genetic loci associated with T1bD patients. The low PRS cases may include MODY patients, there are no MODY mutation identified with genome-wide significance in this GWAS study, which is as expected while generation sequencing, e.g. whole exome sequencing, is the more proper approach

Methods

Results

Conclusion