Methylome-Wide Association Study of Obsessive-Compulsive Disorder

Background Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition influenced by both genetic and environmental risk factors. Epigenetic modifications, such as DNA methylation, may offer insights into biologically meaningful differences associated with the disorder.

We conducted the largest methylome-wide association study (MWAS) of OCD to date, analyzing saliva DNA samples from 414 individuals with OCD and 384 controls using the Illumina EPICv2 array. Differentially methylated positions (DMPs) and regions (DMRs) were identified, with additional analyses including sex-stratified comparisons, methylation quantitative trait loci (mQTL) mapping, and assessments of cell-type composition differences.

We identified 35 DMPs and 17 DMRs associated with OCD, mapping to genes involved in neurotransmission, neurodevelopment, synaptic function, and gene regulation. Sex-stratified analyses revealed additional sex-specific methylation signals, highlighting biological differences between males and females. Most associated loci were influenced by genetic variation (mQTLs). Differences in estimated cell composition and the identification of immune-related genes suggest a potential role for immune system processes. Correlation analyses between brain and saliva methylation indicated that several findings may reflect brain-relevant biology.

Our findings emphasize the importance of integrating epigenetic, genetic, and sex-specific data to advance our understanding of OCD. DNA methylation may ultimately contribute to progress toward clinically relevant precision medicine approaches. Competing Interest Statement CR (NORDiC) receives royalties for books or book chapters to Natur och Kultur, Studentlitteratur and Albert Bonniers Foerlag, outside the submitted work. TK received consulting fees from Alkermes Inc. JH has received speaker fees from Medice unrelated to the present work. All other authors report no competing interests. Funding Statement This research was made possible by the generous financial support of the Trond Mohn Foundation. KDH received a fellowship from the University of Bergen, and AKS and SLH were supported by a Bedrehelse grant (#273446). The collection of control samples was funded by grants from the Research Council of Norway and Helse Vest. 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: The study was approved by the Regional Committee of Medical Research Ethics (REK Vest; #2019/1097, #2018/52, #2013/543). All participants provided written informed consent. 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 Data Availability All scripts are available on GitHub (https://github.com/KiraHoeffler/OCD_MWAS). Due to ethical restrictions and data privacy regulations, individual-level data cannot be shared.