文献类型： 外文期刊

作者： Luo, Jie ¹ ; Li, Ling ² ; Niu, Mingming ³ ; Kong, Dehui ² ; Jiang, Yi ⁵ ; Poudel, Suresh ⁶ ; Shieh, Annie W. ⁷ ; Cheng, Lijun ⁷ ; Giase, Gina ⁷ ; Grennan, Kay ⁷ ; White, Kevin P. ⁸ ; Chen, Chao ⁹ ; Wang, Sidney H. ¹¹ ; Pinto, Dalila ¹² ; Wang, Yue ¹³ ; Liu, Chunyu ¹⁴ ; Peng, Junmin ³ ; Wang, Xusheng ² ;

作者机构： 1.Zhejiang Acad Agr Sci, State Key Lab Managing Biot & Chem Threats Qual &, Hangzhou 310021, Zhejiang, Peoples R China

2.Univ Tennessee, Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN 38103 USA

3.St Jude Childrens Res Hosp, Dept Struct Biol, Memphis, TN 38105 USA

4.St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

5.Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Epidemiol & Biostat, Wuhan 430030, Hubei, Peoples R China

6.St Jude Childrens Res Hosp, Ctr Prote & Metabol, Memphis, TN 38105 USA

7.Univ Chicago, Knapp Ctr Biomed Discovery, Chicago, IL 60637 USA

8.Natl Univ, Dept Biochem & Precis Med, Singapore 119077, Singapore

9.Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410083, Hunan, Peoples R China

10.Cent South Univ, Sch Life Sci, Human Key Lab Med Genet, Changsha 410083, Hunan, Peoples R China

11.Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77030 USA

12.Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

13.Virginia Polytech Inst & State Univ, Arlington, VA 22203 USA

14.SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA

期刊名称：MOLECULAR PSYCHIATRY （ 影响因子：11.0； 五年影响因子：11.9 ）

ISSN： 1359-4184

年卷期： 2024 年

页码：

收录情况： SCI

摘要： Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate <5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.