Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients.
Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients.
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DOI：
10.1038/s41598-021-94994-9
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发表时间：
2021-08-06
影响因子：
4.6
通讯作者：
Hakonarson H
中科院分区：
文献类型：
--
作者：
Qu J;Qu HQ;Bradfield JP;Glessner JT;Chang X;Tian L;March M;Connolly JJ;Roizen JD;Sleiman PMA;Hakonarson H
本研究采用自身免疫性1型糖尿病（T1 D）多基因风险评分（PRS），筛选低PRS的T1 D患者，并寻找这些患者的易感基因。我们的假设是，非主流（或非自身免疫性）T1 D的遗传效应（可能由相对罕见的遗传变异介导）可能在以前对T1 D病例的研究中被稀释。分别包括用于PRS建模和检验的两个队列。第一队列包括3302例T1 D病例和6181例对照，独立的第二队列包括3297例T1 D病例和6169例对照。使用PRSice-2识别出T1 D PRS较低的病例，并通过全基因组关联（GWA）测试与T1 D PRS较低的对照组进行比较。13个高插补质量的新遗传位点（质量评分r2 > 0.91），在全基因组显著性上鉴定出与低PRS T1 D相关的SNP/SNV（P ≤ 5.0 × E−08），除了4个已建立的T1 D基因座，3个我们以前研究报告的基因座，以及9个以罕见SNV为代表的潜在新基因座外，但插补质量相对较低（质量分数r2 < 0.90）。在这13个新基因座中，已有9个区域与肥胖相关性状相关。3个基因座编码长基因间非蛋白质编码RNA（lncRNA），2个基因座参与N-连接糖基化也突出显示在这项研究中。
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.
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