Background: Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts have mostly been restricted to locus-based methods that ignore information from the rest of the genome. Methods: To more accurately characterize genes involved in schizophrenia etiology, we applied a combination of highly-predictive tools to a published GWAS of 67,390 schizophrenia cases and 94,015 controls. We combined both locus-based methods (fine-mapped coding variants, distance to GWAS signals) and genome-wide methods (PoPS, MAGMA, ultra-rare coding variant burden tests). To validate our findings, we compared them with previous prioritization efforts, known neurodevelopmental genes, and results from the PsyOPS tool. Results: We prioritized 62 schizophrenia genes, 41 of which were also highlighted by our validation methods. In addition to DRD2, the principal target of antipsychotics, we prioritized 9 genes that are targeted by approved or investigational drugs. These included drugs targeting glutamatergic receptors (GRIN2A and GRM3), calcium channels (CACNA1C and CACNB2), and GABAB receptor (GABBR2). These also included genes in loci that are shared with an addiction GWAS (e.g. PDE4B and VRK2). Conclusions: We curated a high-quality list of 62 genes that likely play a role in the development of schizophrenia. Developing or repurposing drugs that target these genes may lead to a new generation of schizophrenia therapies. Rodent models of addiction more closely resemble the human disorder than rodent models of schizophrenia. As such, genes prioritized for both disorders could be explored in rodent addiction models, potentially facilitating drug development.

JK, AB, SA, GP, MS, NB, DP, and SR have nothing to disclose. AFP reports receiving a grant from Akrivia Health for a project unrelated to this submission. KH is a former employee of 23andMe, Inc. and owns 23andMe, Inc. stock options.

JK and SR were supported by the German Center for Mental Health (DZPG). AB; JK; AFP; and SR were supported by the European Union's Horizon program (101057454; "PsychSTRATA"). AB and SR were supported by The German Research Foundation (402170461; grant "TRR265"). DP and MS were supported by The Netherlands Organization for Scientific Research (NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology - Grant No. 024.004.012). DP was supported by The European Research Council (Advanced Grant No ERC-2018-AdG GWAS2FUNC 834057). AFP; NB; and DP were supported by the European Union's Horizon program (964874; "REALMENT"). AFP was supported by an Academy of Medical Sciences "Springboard" award (SBF005\1083). KH was supported by a Humboldt Research Fellowship from the Alexander von Humboldt Foundation. GP; SA; DP; SR; and the research reported in this publication were supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number R01MH124873. The content is the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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:

The PGC3 GWAS core dataset is available through the PGC data access portal: https://pgc.unc.edu/for-researchers/data-access-committee/data-access-portal/ Summary statistics of the PGC3 GWAS are freely available for download: https://pgc.unc.edu/for-researchers/download-results/

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