Epigenetic Mechanisms Regulating the Association between OR2L13 and Major Psychiatric Disorders

Abstract Background Previously, population-based cohort studies have identified the association between epigenetic modifications of OR2L13 related to mental disorders and Gestational diabetes mellitus (GDM). However, the causal nature of these associations remains difficult to establish owing to confounding. Aims The purpose of the study was to investigate the causal effect of methylation of OR2L13 and offspring mental health outcomes. Method We performed two-sample mendelian randomisation to assess the effect of methylation of OR2L13 on mental disorders. Methylation of 7 CpG sites within OR2L13 related to GDM from two previous studies were used as exposure. Genome wide significant single nucleotide polymorphisms for methylation of OR2L13 retrieved from published data were used as instrumental variables. Their causal impact on major psychiatric disorders was assessed using summary-level data mostly from the Psychiatric Genomics Consortium. Results Lower OR2L13 methylation was casually associated with a higher risk of PD in offspring [cg03748376: odds ratio (OR)=0.81, 95% confidence interval (CI) =0.68-0.97, P =0.02]. However, little evidence was found for a causal relationship between the methylation levels of OR2L13 and autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD) and obsessive-compulsive disorder (OCD). Conclusions Evidence from our study supported a causal effect of lower OR2L13 methylation on PD risk. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by grants from the National Natural Science Foundation of China (82125032, 81930095, 81761128035 and 82373588), the Science and Technology Commission of Shanghai Municipality (19410713500, 2018SHZDZX01 and 23YF1425700), the Shanghai Municipal Commission of Health and Family Planning (GWV-10.1-XK07, 2020CXJQ01, 2018YJRC03), the Shanghai Clinical Key Subject Construction Project (shslczdzk02902), Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20211100), the Guangdong Key Project (2018B030335001). ### 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: 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 All data produced in the present work are contained in the manuscript