{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:52:06Z","timestamp":1788317526924,"version":"build-2803163510"},"posted":{"date-parts":[[2025,12,23]]},"group-title":"Genetic and Genomic Medicine","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Obsessive-compulsive disorder (OCD) affects 2-3% of the population with often disabling obsessions and compulsions. Despite its high heritability, genetic studies of OCD have lagged other psychiatric disorders, particularly in understanding the role of rare genetic variants.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To identify rare coding genetic variants contributing to OCD risk and examine genetic overlap with chronic tic disorders (CTD) and other psychiatric conditions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Family-based and case-control whole-exome sequencing (WES) study.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Settings<\/jats:title>\n                  <jats:p>WES data were aggregated from 11 independent cohorts across Sweden, the United States, and the United Kingdom.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>A total of 47,194 individuals were available, and 44,089 passed quality control for analysis. The final sample included 6,071 individuals with OCD, comprising 1,202 probands from family-based trios and 4,869 cases, and 38,018 controls.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposures<\/jats:title>\n                  <jats:p>Rare damaging coding variants identified by WES.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>Identification of OCD risk genes through rare variant analyses, meta-analysis with CTD data, gene-set enrichment analyses, and evaluation of cross-disorder genetic overlap using curated gene sets.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The analysis provided an estimate of approximately 470 autosomal genes contributing to OCD risk through rare genetic variation.\n                    <jats:italic>CHD8<\/jats:italic>\n                    reached genome-wide significance (q &lt; 0.05). Meta-analysis with CTD data revealed additional risk genes, including\n                    <jats:italic>CELSR3<\/jats:italic>\n                    (q &lt; 0.05),\n                    <jats:italic>QRICH1<\/jats:italic>\n                    , and\n                    <jats:italic>WWC1<\/jats:italic>\n                    (q &lt; 0.1). We observed significant genetic overlap between OCD, autism spectrum disorder (ASD), and developmental delay: 33% of ASD genes with FDR &lt; 0.1 showed association with OCD (p &lt; 0.001), and 36% showed possible associations in the shared OCD-CTD genetic architecture (p &lt; 0.001), but minimal rare-variant overlap with bipolar disorder and schizophrenia risk genes. We also found that\n                    <jats:italic>CHD8-<\/jats:italic>\n                    regulated genes were enriched for both rare and common variant associations with OCD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>\n                    In this largest study to date of rare coding variation in OCD, we confirm\n                    <jats:italic>CHD8<\/jats:italic>\n                    as the first genome-wide significant rare-variant risk gene, show that genes that are targets of\n                    <jats:italic>CHD8<\/jats:italic>\n                    can carry rare and common variant risk for OCD, and identify multiple additional genes and pathways contributing to risk. Taken together, the findings show that OCD shares substantially greater genetic overlap with neurodevelopmental conditions than with adult-onset psychiatric disorders, refining the developmental framework of OCD and informing future mechanistic and clinical research.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Question<\/jats:title>\n                    <jats:p>How do rare genetic variants contribute to OCD, and how do they overlap with variants linked to chronic tic disorders (CTD) and other neurodevelopmental conditions?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      Exome sequencing of 6,071 OCD cases demonstrated significant enrichment of rare damaging variants in evolutionarily conserved genes, and\n                      <jats:italic>CHD8<\/jats:italic>\n                      emerged as the first genome-wide significant OCD risk gene. Rare variant patterns in OCD and CTD aligned with those seen in neurodevelopmental, but not adult-onset psychiatric disorders, indicating shared neurodevelopmental pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>\n                      These findings clarify OCD\u2019s neurodevelopmental genetic architecture, identify\n                      <jats:italic>CHD8<\/jats:italic>\n                      as a key risk pathway, and reveal overlap with CTD and other conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.22.25342827","type":"posted-content","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T20:40:11Z","timestamp":1766522411000},"source":"Crossref","is-referenced-by-count":3,"title":["Rare coding variation in OCD implicates shared genes with other 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