{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T19:41:29Z","timestamp":1777146089857,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,22]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Obsessive compulsive disorder (OCD) is significantly heritable, but only a fraction of the contributory genetic variation has been identified, and the molecular etiology involved remains obscure. Identifying rare contributory variants of large effect would be an important milestone in helping to elucidate the mechanisms involved. Analysis of densely affected pedigrees is a potentially useful strategy to bypass the sample size challenges of standard case-control approaches. Here we performed whole genome sequencing (WGS) of 25 individuals across two multiplex OCD pedigrees. We prioritised rare variants using a Bayesian inference approach which incorporates variant pathogenicity and co-segregation with OCD. In the first pedigree, we identified a highly deleterious missense variant in\n                  <jats:italic>NPY5R<\/jats:italic>\n                  , carried by the majority of affected individuals. This gene is brain-expressed and has previously been implicated in panic disorder and internet addiction GWAS studies. In the second pedigree, we identified a large deletion of\n                  <jats:italic>DLGAP1<\/jats:italic>\n                  and a missense variant in\n                  <jats:italic>MAPK8IP3<\/jats:italic>\n                  , that perfectly co-segregated in a specific branch of the family: both genes have previously been implicated in OCD and autism. Both genes contribute to a protein interaction network including\n                  <jats:italic>ERBB4<\/jats:italic>\n                  and\n                  <jats:italic>RAPGEF1<\/jats:italic>\n                  which we had previously identified in a large Tourette Syndrome pedigree. Our analysis suggests that both energy homeostasis and downstream signalling from the post-synaptic density may both be important avenues for future research.\n                <\/jats:p>","DOI":"10.64898\/2026.04.21.26350600","type":"posted-content","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T16:40:16Z","timestamp":1776876016000},"source":"Crossref","is-referenced-by-count":0,"title":["Rare protein-disrupting variants in\n                  <i>NPY5R, DLGAP1<\/i>\n                  and\n                  <i>MAPK8IP3<\/i>\n                  segregate with OCD in two multiplex pedigrees"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-0508","authenticated-orcid":false,"given":"Cathal","family":"Ormond","sequence":"first","affiliation":[{"name":"Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathieu","family":"Cap","sequence":"additional","affiliation":[{"name":"Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Chieh","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, McKnight Brain Institute, Center for OCD, Anxiety, and Related Disorders, University of Florida, Gainesville, Florida, United States of America"},{"name":"University of Florida Genetics Institute, University of Florida, Gainesville, Florida, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9773-2248","authenticated-orcid":false,"given":"Niamh","family":"Ryan","sequence":"additional","affiliation":[{"name":"Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6403-2509","authenticated-orcid":false,"given":"Denise","family":"Chavira","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of California Los Angeles, Los Angeles, California, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon E","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Behavioral Neuroscience, University of Chicago, Chicago, Illinois, United States of 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