Genetic discovery and risk prediction for type 1 diabetes in individuals without high-risk HLA-DR3/DR4 haplotypes

medRxiv (Cold Spring Harbor Laboratory) Pub Date : 2023-11-12 DOI:10.1101/2023.11.11.23298405

Carolyn McGrail, Joshua Chiou, Ruth Elgamal, Amber Luckett, Richard Oram, Paola Benaglio, Kyle Gaulton

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Abstract

Over 10% of individuals with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes, and whether they carry distinct genetic risk is unknown. To identify genetic drivers of T1D in the absence of DR3/DR4, we performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. We identified risk variants at the MHC locus and genome-wide with evidence for heterogeneity in effects on T1D compared to DR3/DR4. T1D-associated variants in non-DR3/DR4 individuals were enriched for loci, regulatory elements, and pathways related to antigen presentation, innate immunity, and beta cells, and depleted in T cells, compared to DR3/DR4. Most non-DR3/DR4 T1D cases are poorly classified based on the existing T1D GRS2, and we created a new GRS which highly discriminated non-DR3/DR4 T1D from non-diabetes and T2D and outperformed GRS2. In total we identified heterogeneity in T1D genetic risk dependent on high-risk HLA haplotype which revealed distinct disease mechanisms and enabled more accurate risk prediction for T1D a non-DR3/DR4 background.

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无高危HLA-DR3/DR4单倍型个体1型糖尿病的遗传发现和风险预测

超过10%的1型糖尿病(T1D)患者没有高风险的HLA-DR3或-DR4单倍型，他们是否携带明显的遗传风险尚不清楚。为了确定在DR3/DR4缺失的情况下T1D的遗传驱动因素，我们对12,316个非DR3/DR4样本进行了T1D关联和精细定位分析。我们确定了MHC位点和全基因组的风险变异，与DR3/DR4相比，对T1D的影响存在异质性。与DR3/DR4相比，非DR3/DR4个体的t1d相关变异在基因座、调控元件和与抗原呈递、先天免疫和β细胞相关的途径上富集，而在T细胞中则缺失。大多数非dr3 /DR4 T1D病例基于现有的T1D GRS2分类较差，我们创建了一个新的GRS，该GRS高度区分非dr3 /DR4 T1D与非糖尿病和T2D，并且优于GRS2。总的来说，我们确定了T1D遗传风险依赖于高危HLA单倍型的异质性，这揭示了不同的疾病机制，并能够更准确地预测非dr3 /DR4背景的T1D风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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medRxiv (Cold Spring Harbor Laboratory)

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