Breunig Sophie, Lee Younga Heather, Karlson Elizabeth W, Krishnan Arjun, Lawrence Jeremy M, Schaffer Lukas S, Grotzinger Andrew D
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO USA.
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO USA.
medRxiv. 2024 Jul 19:2024.07.18.24310651. doi: 10.1101/2024.07.18.24310651.
Autoimmune and autoinflammatory diseases have been linked to psychiatric disorders in the phenotypic and genetic literature. However, a comprehensive model that investigates the association between a broad range of psychiatric disorders and immune-mediated disease in a multivariate framework is lacking.
This study aims to establish a factor structure based on the genetic correlations of immune-mediated diseases and investigate their genetic relationships with clusters of psychiatric disorders.
We utilized Genomic Structural Equation Modeling (Genomic SEM) to establish a factor structure of 11 immune-mediated diseases. Genetic correlations between these immune factors were examined with five established factors across 13 psychiatric disorders representing compulsive, schizophrenia/bipolar, neurodevelopmental, internalizing, and substance use disorders. We included GWAS summary statistics of individuals of European ancestry with sample sizes from 1,223 cases for Addison's disease to 170,756 cases for major depressive disorder.
Genetic correlations between psychiatric and immune-mediated disease factors and traits to determine genetic overlap. We develop and validate a new heterogeneity metric, , that quantifies the degree to which factor correlations are driven by more specific pairwise associations. We also estimate residual genetic correlations between pairs of psychiatric disorders and immune-mediated diseases.
A four-factor model of immune-mediated diseases fit the data well and described a continuum from autoimmune to autoinflammatory diseases. The four factors reflected autoimmune, celiac, mixed pattern, and autoinflammatory diseases. Analyses revealed seven significant factor correlations between the immune and psychiatric factors, including autoimmune and mixed pattern diseases with the internalizing and substance use factors, and autoinflammatory diseases with the compulsive, schizophrenia/bipolar, and internalizing factors. Additionally, we find evidence of divergence in associations within factors as indicated by . This is further supported by 14 significant residual genetic correlations between individual psychiatric disorders and immune-mediated diseases.
Our results revealed genetic links between clusters of immune-mediated diseases and psychiatric disorders. Current analyses indicate that previously described relationships between specific psychiatric disorders and immune-mediated diseases often capture broader pathways of risk sharing indexed by our genomic factors, yet are more specific than a general association across all psychiatric disorders and immune-mediated diseases.
在表型和遗传学文献中，自身免疫性疾病和自身炎症性疾病已与精神障碍相关联。然而，缺乏一个在多变量框架下研究广泛精神障碍与免疫介导疾病之间关联的综合模型。
本研究旨在基于免疫介导疾病的遗传相关性建立一个因素结构，并研究它们与精神障碍集群的遗传关系。
设计、设置和参与者：我们利用基因组结构方程模型（Genomic SEM）建立了11种免疫介导疾病的因素结构。在代表强迫性、精神分裂症/双相情感障碍、神经发育障碍、内化性和物质使用障碍的13种精神障碍中，用五个已确定的因素检验了这些免疫因素之间的遗传相关性。我们纳入了欧洲血统个体的全基因组关联研究（GWAS）汇总统计数据，样本量从艾迪生病的1223例到重度抑郁症的170756例不等。
精神障碍和免疫介导疾病因素及性状之间的遗传相关性，以确定遗传重叠。我们开发并验证了一种新的异质性指标 ，它量化了因素相关性由更具体的成对关联驱动的程度。我们还估计了成对精神障碍和免疫介导疾病之间的残余遗传相关性。
免疫介导疾病的四因素模型与数据拟合良好，并描述了从自身免疫性疾病到自身炎症性疾病的连续体。这四个因素反映了自身免疫性、乳糜泻、混合模式和自身炎症性疾病。分析揭示了免疫因素和精神因素之间的七个显著因素相关性，包括自身免疫性和混合模式疾病与内化性和物质使用因素，以及自身炎症性疾病与强迫性、精神分裂症/双相情感障碍和内化性因素。此外，我们发现如 所示的因素内关联存在差异的证据。这得到了个体精神障碍和免疫介导疾病之间14个显著残余遗传相关性的进一步支持。
我们的结果揭示了免疫介导疾病集群与精神障碍之间的遗传联系。当前分析表明，先前描述的特定精神障碍与免疫介导疾病之间的关系通常捕捉到了我们基因组因素所索引的更广泛的风险共享途径，但比所有精神障碍和免疫介导疾病之间的一般关联更具特异性。
