Dog-human gene network colocalization links synaptic signalling and ubiquitination to compulsive disorders
- 1Uppsala University
Abstract
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. Pet dogs develop a compulsive disorder (dogCD) similar to OCD. 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, 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.
Related
- Enhanced Synaptic-Related Transcriptional Programs in Human Forebrain Organoids for Modeling Synaptopathy-Associated Neurodevelopmental Disorders
- IL-33/ST2 signalling in pediatric food allergy and eosinophilic gastrointestinal disorders: a systematic review of human and preclinical evidence
- Associations of Blood Lipid Traits with Cognitive-Related Outcomes and Their Sensitivity to APOE-Region Instrumental Variables: A Mendelian Randomization and Colocalization Study
- Colocalization between bone loading and metabolic activity in the human tibia in response to acute exercise
- TileScope quantifies spatial gene expression relationships beyond colocalization
BibTeX
@misc{tengvall2026doghuman,
title = {{Dog-human gene network colocalization links synaptic signalling and ubiquitination to compulsive disorders}},
author = {K. Tengvall and V. Sohrab and M. J. Christmas and G. Brander and E. Pederson and R. Pensch and B. Kenney and C. Song and O. Wallerman and E. Sundstrom and C. Wang and A. Karlsson and L. L. Monsen and Nordic OCD and Related Disorders Consortium (NORDiC) and PGC TS/OCD working group and K. A. Lord and N. I. Strom and C. Ruck and D. Mataix-Cols and M. Mattheisen and J. J. Crowley and J. R. S. Meadows and E. Karlsson and K. Lindblad-Toh},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758413},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758413v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Dog-human gene network colocalization links synaptic signalling and ubiquitination to compulsive disorders
AU - K. Tengvall
AU - V. Sohrab
AU - M. J. Christmas
AU - G. Brander
AU - E. Pederson
AU - R. Pensch
AU - B. Kenney
AU - C. Song
AU - O. Wallerman
AU - E. Sundstrom
AU - C. Wang
AU - A. Karlsson
AU - L. L. Monsen
AU - Nordic OCD and Related Disorders Consortium (NORDiC)
AU - PGC TS/OCD working group
AU - K. A. Lord
AU - N. I. Strom
AU - C. Ruck
AU - D. Mataix-Cols
AU - M. Mattheisen
AU - J. J. Crowley
AU - J. R. S. Meadows
AU - E. Karlsson
AU - K. Lindblad-Toh
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758413
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758413v1
AB - 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. Pet dogs develop a compulsive disorder (dogCD) similar to OCD. 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, 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.
ER -