Identifying potential risk genes and pathways for neuropsychiatric and substance use disorders using intermediate molecular mediator information

Neuropsychiatric and substance use disorders (NPSUD) have a complex etiology that includes environmental and polygenic risk factors with significant cross-trait rG. Genome Wide Association Studies (GWAS) of NPSUD yield numerous association signals. However, for most of these regions, we do not yet have a firm understanding of either the specific risk variants or the effects of these variants. Post-GWAS methods allow researchers to use GWAS summary statistics and functional genomics data to infer the likely molecular mediators (transcript, protein and methylation abundances) for the effect of variants on disorders. One group of post-GWAS approaches is commonly referred to as transcriptome/proteome/methylome wide association studies, which are abbreviated as T/P/MWAS (or collectively as XWAS). Since these approaches use biological mediators, the multiple testing burden is reduced to the number of genes (∼20,000) instead of millions GWAS SNPs leading to increased signal detection. In this work, our aim is to uncover likely risk genes for NPSUD by performing XWAS analyses in two tissues – blood and brain. Firstly, XWAS using the Summary-data based Mendelian Randomization (SMR), which takes GWAS summary statistics, reference xQTL data and a reference LD panel as inputs, was conducted to identify putative causal risk genes. Second, given the large comorbidities among NPSUD and the shared cis-xQTLs between blood and brain, we improved XWAS signal detection in NPSUD for underpowered analyses by performing joint concordance analyses between XWAS results i) across the two tissues and ii) across NPSUD. All XWAS signals i) were adjusted for HEIDI (non-causality) p-values and ii) used to test for pathway enrichment. The results suggest that there were widely shared gene/protein signals within the Major Histocompatibility (MHC) region on chromosome 6 ( BTN3A2 and C4A) and elsewhere in the genome ( RERE, FURIN, ZDHHC5 and NEK4 ). The identification of putative molecular genes and pathways underlying risk may offer new targets for therapeutic development. Some of our analyses’ more immediate actionable signals might relate to vitamins, i.e., i) in KYAT3 (a part of the kynurenine pathway with vitamin B6 as a cofactor) for post-traumatic stress disorder and ii) omega-3 and vitamin D pathways for bipolar disorder. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Research in this work was funded by AA022537 (Huseyin Gedik, Brian P. Riley, and Silviu-Alin Bacanu), R01MH118239 and R01DA052453 (Vladimir I. Vladimirov and Silviu-Alin Bacanu). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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 study are available upon reasonable request to the authors