Genome-wide analyses reveal widespread genetic overlap between neurological and psychiatric disorders and a convergence of biological associations related to the brain

Neurological and psychiatric disorders are considered to reflect distinct underlying pathogenic entities. However, the extent to which they share genetic influences remains unclear. Here, we performed a comprehensive analysis of GWAS data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic risk and biological underpinnings. Using complementary statistical tools, we demonstrate extensive genetic overlap across the disorders, with varying degrees of genetic correlations. In particular, migraine, essential tremor, stroke and multiple sclerosis were genetically correlated with several psychiatric disorders. Biological interrogation indicated heterogenous biological processes associated with neurological diseases, while psychiatric disorders consistently implicated neuronal biology. Altogether, the study demonstrates that neurological and psychiatric disorders are not genetically disparate, but share key etiological aspects, which have important implications for disease classification, clinical practice, and genomic precision medicine. ### Competing Interest Statement O.A.A. has received a speaker honorarium from Lundbeck, Sunovion and Janssen and is a consultant for Cortechs.ai. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board. He is also a member of the Scientific Advisory Board of Healthlytix and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Remaining authors have nothing to disclose. ### Funding Statement We thank the research participants, employees and researchers of the UK Biobank, 23andMe, Inc., MVP, iPSYCH and the many consortia for making this research possible. This research has been conducted using the UK Biobank Resource under Application Number 27412. Moreover, the research has been conducted using and data from MVP, under dbGap accession number phs001672. This work was partly performed on the TSD (Services for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT). Computations were also performed on resources provided by UNINETT Sigma2, the National Infrastructure for High Performance Computing and Data Storage in Norway. We gratefully acknowledge support from the American National Institutes of Health (NS057198, EB000790, 1R01MH124839, R01MH120219, RF1AG073593), the Research Council of Norway (RCN) (229129, 213837, 324252, 300309, 273291, 223273, 248980, 326813), the South-East Norway Regional Health Authority (2019-108, 2022-073), KG Jebsen Stiftelsen (SKGJ-MED-021), EAA grant (#EEA-RO-NO-2018-0573). This project has received funding from the European Union Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874 and 801133 (Marie Sklodowska-Curie grant agreement). ### 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: Each sample was collected with the participants written informed consent and with approval by local institutional review boards. The use of summary statistics for genetic analysis was evaluated by The Norwegian Institutional Review Board: Regional Committees for Medical and Health Research Ethics (REC) South-East Norway and found that no additional ethical approval was required because no individual data were used. 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