Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia

作者全名：Tao, Yiming; Zhao, Rui; Yang, Bin; Han, Jie; Li, Yongsheng

作者地址：[Tao, Yiming; Yang, Bin; Li, Yongsheng] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Intens Care Med, Wuhan 430030, Peoples R China; [Tao, Yiming] Shandong First Med Univ, Shandong Prov Hosp, Dept Crit Care Med, Jinan 250101, Shandong, Peoples R China; [Zhao, Rui] Chongqing Med Univ, Afliated Hosp 1, Dept Lab Med, Chongqing 400042, Peoples R China; [Han, Jie] Qingdao Univ, Qingdao Municipal Hosp, Sch Med, Dept Emergency, Qingdao 266071, Peoples R China

通信作者：Li, YS (通讯作者)，Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Intens Care Med, Wuhan 430030, Peoples R China.; Han, J (通讯作者)，Qingdao Univ, Qingdao Municipal Hosp, Sch Med, Dept Emergency, Qingdao 266071, Peoples R China.

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001205541500001

JCR分区：Q1

影响因子：6.1

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Anxiety; Depression; Schizophrenia; Shared genetic architecture; Drug targets

摘要：Background Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies.Methods We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia. Utilizing GTEx V8 eQTL and deCODE Genetics pQTL data, we performed a three-step summary-data-based Mendelian randomization (SMR) and protein-protein interaction analysis. This helped assess causal and comorbid loci for these disorders and determine if identified loci share coincidental variations with psychiatric diseases. Additionally, phenome-wide association studies, drug prediction, and molecular docking validated potential drug targets.Results We found genetic correlations between anxiety, depression, and schizophrenia, and under a meta-analysis of MR from multiple databases, the causal relationships among these disorders are supported. Based on this, three-step SMR and colocalization analyses identified ITIH3 and CCS as being related to the risk of developing depression, while CTSS and DNPH1 are related to the onset of schizophrenia. BTN3A1, PSMB4, and TIMP4 were identified as comorbidity loci for both disorders. Molecules that could not be determined through colocalization analysis were also presented. Drug prediction and molecular docking showed that some drugs and proteins have good binding affinity and available structural data.Conclusions Our study indicates genetic correlations and shared risk loci between anxiety, depression, and schizophrenia. These findings offer insights into the underlying mechanisms of their comorbidities and aid in drug development.

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