BACKGROUND Previous studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders and investigated the genetic basis of overall autoimmune disease. METHODS We used diagnostic information from patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort. RESULTS Of 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1,383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (P=2.67×10-7, OR=1.38, 95%CI=1.22-1.56), with an overall bidirectional association, wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR=1.13, 95%CI: 1.07-1.21, P=7.95×10-5) and vice versa (HR=1.27, 95%CI=1.16-1.39, P=8.77×10-15). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR=1.01, 95%CI: 1.00-1.02, p=0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P=2.74 × 10-36, OR=1.80, 95% CI: 1.64-1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P=1.43×10-8, OR=10.65, 95%CI=3.21-35.36). CONCLUSIONS Our findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.

中文翻译：

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自身免疫与精神障碍双向关系的遗传因素——丹麦人口研究的结果

背景 先前的研究表明自身免疫和精神障碍之间存在双向性。然而，一直缺乏支持这两种疾病同时发生的遗传研究。在这项研究中，我们检查了自身免疫性和精神障碍之间关联的潜在遗传贡献，并调查了整体自身免疫性疾病的遗传基础。方法 我们使用来自丹麦基于人群的病例队列样本 (iPSYCH2012) 的 7 种自身免疫性疾病和 6 种精神障碍患者的诊断信息。我们使用生存分析探索了流行病学关联，并对多基因风险评分 (PRS) 对自身免疫和精神疾病的影响进行了建模。在 iPSYCH 队列中使用 GWAS 和估算的 HLA 等位基因研究遗传因素。结果 64,039 个人，总共 43，902 人（68.6%）被诊断为精神障碍，1,383 人（2.2%）被诊断为自身免疫性疾病。两种疾病类别之间存在显着的合并症（P=2.67×10-7，OR=1.38，95%CI=1.22-1.56），总体呈双向关联，其中自身免疫性疾病患者发生后续精神疾病的风险增加障碍（HR=1.13，95%CI：1.07-1.21，P=7.95×10-5），反之亦然（HR=1.27，95%CI=1.16-1.39，P=8.77×10-15）。将 PRS 添加到这些调整模型中不会对关联产生影响。自身免疫性疾病的 PRS 与精神障碍风险的增加仅略微相关（HR=1.01，95%CI：1.00-1.02，p=0.038），而精神障碍的 PRS 总体上与自身免疫性疾病无关。我们的 GWAS 突出显示了 6 号染色体上的 12 个基因座（最小 P=2.74 × 10-36，OR=1.80，95% CI：1.64-1.96），通过生物信息学功能分析涉及基因调控，从而确定整体自身免疫性疾病的新候选基因。此外，我们观察到 20 个人类白细胞抗原 (HLA) 等位基因与整体自身免疫性疾病密切相关，但我们没有发现它们与整体精神障碍相关的重要证据。自身免疫性疾病和精神障碍共病诊断的 GWAS 也在 7 号染色体上鉴定了全基因组显着位点（P=1.43×10-8，OR=10.65，95%CI=3.21-35.36）。结论我们的研究结果证实了自身免疫性疾病和精神障碍之间的整体共病性和双向性，并确定了与整体自身免疫性疾病显着相关的 HLA 基因。此外，