Kira D. Höffler, Kira D. Höffler, Anne-Kristin Stavrum, Matthew W. Halvorsen, Thorstein Olsen Eide, Kristen Hagen, André Høberg, Julia Bäckman, Long Long Chen, James J. Crowley, Elles de Schipper, Diana Pascal, Jan Haavik, Kristen Hagen, Matthew Halvorsen, Bjarne Hansen, Kira D. Höffler, Kira D. Höffler, Fred Johansson, Elinor K. Karlsson, Gerd Kvale, Paul Lichtenstein, Kerstin Lindblad-Toh, Manuel Mattheisen, David Mataix-Cols, Christian Rück, Thorstein Olsen Eide, Nora I. Strom, John Wallert, Gerd Kvale, James J. Crowley, Jan Haavik, Kerry J. Ressler, Bjarne Hansen, Torsten Klengel, Stéphanie Le Hellard
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. METHODS: We conducted the largest methylome-wide association study of OCD to date, analyzing saliva DNA samples from 414 adults with OCD (297 female, 117 male) and 384 adult control participants (275 female, 109 male) using the Illumina EPICv2 array. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were identified, with additional analyses including sex-stratified comparisons, methylation quantitative trait loci (mQTL) mapping, and assessments of differences in cell type composition. RESULTS: 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. CONCLUSIONS: 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.