Integration of tissue-specific multi-omics data implicates brain targets for complex neuropsychiatric traits

Genome-wide association studies (GWAS) have uncovered genetic variants susceptible to brain disorders. However, due to the complex pathogenesis of these diseases and heterogeneity of the brain tissues, how and through which the genetic variants confer risk for brain abnormalities and brain disorders remain elusive, especially from a multi-omics perspective and in the context of brain regions. In this study, we integrated brain region-specific transcriptomics, proteomics, and imaging genetics data by systematically applying transcriptome- and proteome-wide association analysis, Mendelian randomization, and Bayesian colocalization methods. At both gene expression and protein abundance levels, this integrative study identified 51 associations linking 42 targets to structural alterations of 10 brain regions. Additionally, we validated the causal effects of 20 identified genes on one or more brain disorders. Our analysis further illuminated the significant enrichment of 12 targets in five main types of brain cells. Overall, this study underscored the utility of a multi-omics and region-specific approach in understanding the pathogenesis of complex brain abnormalities and brain disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported in part by the National Natural Science Foundation of China (62103116, 62102115), the Shandong Provincial Natural Science Foundation (2022HWYQ-093), the Natural Science Foundation of Heilongjiang Province (LH2022F016), and by the Fundamental Research Funds for the Central Universities (3072022TS2614, 79000010, 79000011). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: State that source data were openly available before the initiation of the study and describe how they can be located by providing links to all download pages of the original data sources I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript