Clinical and public health research has revealed the co-occurrence of several neuropsychiatric diseases among patients with celiac disease (CD). The significant presence of CD-specific autoantibodies in patients with neuropsychiatric diseases and vice versa are often reported. To explain the genetic basis of such frequent disease co-occurrence and investigate the underlying common pathways/processes, we performed an extensive cross-disease association study followed by supporting in silico functional validation of the leads. Genomewide association study (GWAS) data for CD and eight commonly co-occurring neuropsychiatric diseases from Caucasian populations were analysed, and the shared loci were determined. We performed Immunochip-based fine mapping of these overlapping association signals in an independent European CD data and tested their cross-ethnic transferability using CD association data from the genetically distinct north Indian population. This study identified 12 shared loci between the two diseases with genomewide significance (P ≤ 5e-8). Of these five loci, namely NFIA, KIA1109, NOTCH4-TSBP1-PBX2, HLA-DQA1 and CSK replicated in an independent Dutch cohort representing European ancestry. Three of these loci, namely NFIA, NOTCH4-TSBP1-PBX2 and HLA-DQA1 that are common between CD, anxiety, migraine and schizophrenia respectively withstood locus transferability test in north Indians. Tissue-specific eQTL analysis of SNPs from transferable loci revealed expression QTL effects in brain tissue besides the small intestine and whole blood. Pathway analysis and evidence of epigenetic regulation highlighted the potential contribution of these SNPs to disease pathology. The replicable and transferable association of genetic variants from MHC locus and their functional implications suggest the process of antigen presentation and adaptive/innate immune response regulated by non-HLA genes in the locus may dominate the shared pathogenesis of CD and neuropsychiatric diseases. Functional validation of the shared candidate genes is warranted to unravel the molecular mechanism for the co-occurrence of CD and specific neuropsychiatric diseases.

临床和公共卫生研究表明，乳糜泻 (CD) 患者同时患有多种神经精神疾病。经常报道神经精神疾病患者存在 CD 特异性自身抗体，反之亦然。为了解释这种常见疾病并发的遗传基础并研究潜在的共同途径/过程，我们进行了广泛的交叉疾病关联研究，然后进行了计算机支持引线的功能验证。分析了 CD 的全基因组关联研究 (GWAS) 数据和来自高加索人群的八种常见并发神经精神疾病，并确定了共享位点。我们对独立的欧洲 CD 数据中的这些重叠关联信号进行了基于免疫芯片的精细映射，并使用来自基因不同的北印度人口的 CD 关联数据测试了它们的跨种族可转移性。该研究确定了两种疾病之间具有全基因组意义的 12 个共享基因座 ( P  ≤ 5e-8)。在这五个位点中，即NFIA、KIA1109、NOTCH4 - TSBP1 - PBX2、HLA-DQA1和CSK在代表欧洲血统的独立荷兰队列中复制。其中三个位点，即NFIA、NOTCH4 - TSBP1 - PBX2和HLA-DQA1CD、焦虑症、偏头痛和精神分裂症之间常见的特征分别经受住了北印度人的基因座可转移性测试。来自可转移基因座的 SNP 的组织特异性 eQTL 分析揭示了除小肠和全血之外的脑组织中的表达 QTL 效应。通路分析和表观遗传调控的证据突出了这些 SNP 对疾病病理学的潜在贡献。来自 MHC 基因座的遗传变异的可复制和可转移关联及其功能意义表明，由基因座中的非 HLA 基因调节的抗原呈递过程和适应性/先天性免疫反应可能主导 CD 和神经精神疾病的共同发病机制。