Dog-human gene network colocalization links synaptic signalling and ubiquitination to compulsive disorders
Year: 2026
Type: preprint
Abstract: Summary Obsessive-compulsive disorder (OCD) is highly polygenic, and the largest genome-wide association study (GWAS), with 53,660 cases and 2,044,417 controls, identified only 30 loci, a small fraction of loci estimated to explain its heritability – too few to resolve biological pathways 1 . Pet dogs develop a compulsive disorder (dogCD) similar to OCD 2 . In a GWAS of dogCD with 2,584 dogs from the community science project Darwin’s Ark, each dog locus explains at least 40-fold more phenotypic variance than each human OCD locus, giving power equivalent to the human GWAS with 80-fold fewer individuals. Combining the two GWAS identifies a 165-gene network undetectable in humans at current sample sizes. This network is enriched for genes expressed in neurons, particularly in the amygdala and cortex, and comprises four biological processes: excitatory-inhibitory synaptic transmission, axon guidance and neuron recognition, protein ubiquitination, and adenylyl cyclase-activating G-protein-coupled receptor signaling. Like most complex human traits 3 , dogCD risk is likely driven by regulatory variation: fine-mapped dogCD SNPs are non-coding, and dogCD loci are enriched in candidate cis-regulatory elements (cCREs) in a new dog epigenomic atlas spanning eight brain regions. The cross-species network implicates an inherited risk architecture largely outside current OCD pharmacotherapy, and establishes pet dogs as a model for gene network discovery, particularly for conditions underpowered in human studies.
Authors: Katarina Tengvall, Vista Sohrab, Matthew J. Christmas, Gustaf Brander, Eric Pederson, Raphaela Pensch, Brittney Kenney, Chengcheng Song, Ola Wallerman, Elisabeth Sundström, Chao Wang, Åsa Karlsson, Linnéa L. Monsén, PGC TS/OCD working group, Kathryn A. Lord, Nora I. Strom, Christian Rück, David Mataix-Cols, Manuel Mattheisen, James J. Crowley, Jennifer R. S. Meadows, Elinor K. Karlsson, Kerstin Lindblad-Toh
Institutions: Uppsala University, Science for Life Laboratory, Broad Institute, University of Massachusetts Chan Medical School, Region Stockholm, Karolinska Institutet, Stockholm Health Care Services, Humboldt-Universität zu Berlin, Institut für Psychiatrische Phänomik und Genomik, Dalhousie University, Aarhus University, University of North Carolina at Chapel Hill
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: green
Funders: University of Southern California, Vetenskapsrådet, Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Uppsala Universitet, Science for Life Laboratory, National Institutes of Health, University of California, San Diego, Uppsala Multidisciplinary Center for Advanced Computational Science, Center for Innovative Medicine, National Institute on Aging, National Institute of Mental Health, National Human Genome Research Institute
Awards: G1186542468, G1343964538, G1570763554, G1861103606, Old age depression: improving prevention and care by taking into account transitions across the spectrum of depressive symptoms, A multi-species approach to unlock the disease and treatment mechanisms of obsessive-compulsive disorder: Expansion of the World’s largest biobank for novel genomic studies, OCD: Novel Comparative Genomic Approaches to Identify Disease and Treatment Mechanisms, Obsessive-Compulsive Disorder: Novel comparative genomic approaches to identification of disease and treatment mechanisms, G3805817536, Understanding and treating Obsessive-Compulsive and Related Disorders: etiology, epidemiology, treatment development and outcome, Predicting health outcomes and labor market marginalization after treatment in common mental disorders using Machine Learning, PRiMED: Predicting Response to CBT in Mental Disorders using multimodal data and machine learning, The Dog Aging Project: Genetic and Environmental Determinants of Healthy Aging in Companion Dogs, National Bioinformatics Infrastructure Sweden (NBIS) and the Swedish node in ELIXIR (the European infrastructure for biological information), Translating genomic findings for early onset obsessive-compulsive disorder into etiological insights, Mammalian and primate constraint to decipher human genetic disease and cancer, Economic support for invited speakers for the international conference Science@FELs, G6565658171, Genetic & Environmental Predictors of Tourette Syndrome & OCD in Denmark, G796431723, G8089427974, G8107169257, G9000213955
OpenAlex ID: W7213052219