Genetic Inference of On-target and Off-target Side-effects of Antipsychotic Medications

Genetic Inference of On-target and Off-target Side-effects of Antipsychotic Medications | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Genetic Inference of On-target and Off-target Side-effects of Antipsychotic Medications Andrew Elmore, Aws Sadik, Lavinia Paternoster, Golam Khandaker, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4570917/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Adverse side-effects are the primary cause of antipsychotic drug discontinuation rather than poor efficacy. It is often difficult to ascertain whether patient-reported side-effects are caused by a drug, and if so, through which mechanism. Using a novel genetic method we have devised, we investigated evidence of causality and mechanism for 105 reported side-effects of 6 commonly prescribed antipsychotic drugs which target 68 receptors. We used publicly available drug binding affinity data and GWAS summary statistics along with statistical methods including Mendelian randomization and genetic colocalization to devise a representative ‘score’ for each combination of drug, side-effect, and receptor. We show that 48 side-effects are likely caused by drug action through 30 receptors, which are mainly attributable to off-target effects (26 off-target receptors underlying 39 side effects). Of individual drugs, clozapine has the largest cumulative side effect profile (Score = 27.4, SE = 5.2), and the largest number of side-effects (n = 46). We show that two well-known side-effects for clozapine, neutropenia and weight change, are underpinned by the action of GABA and CHRM3 receptors respectively. Our novel genetic approach can map side-effects to drugs and elucidate underlying mechanisms, which could potentially inform clinical practice, drug repurposing, and pharmacological development. Health sciences/Diseases/Psychiatric disorders/Schizophrenia Health sciences/Biomarkers/Predictive markers Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files STROBEMRchecklist.docx supplemental1.docx supplemental2.xlsx Supplemental Tables Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4570917","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":314463435,"identity":"92240d2a-80b2-4f1b-992c-370e39357445","order_by":0,"name":"Andrew 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It is often difficult to ascertain whether patient-reported side-effects are caused by a drug, and if so, through which mechanism. Using a novel genetic method we have devised, we investigated evidence of causality and mechanism for 105 reported side-effects of 6 commonly prescribed antipsychotic drugs which target 68 receptors. We used publicly available drug binding affinity data and GWAS summary statistics along with statistical methods including Mendelian randomization and genetic colocalization to devise a representative \u0026lsquo;score\u0026rsquo; for each combination of drug, side-effect, and receptor. We show that 48 side-effects are likely caused by drug action through 30 receptors, which are mainly attributable to off-target effects (26 off-target receptors underlying 39 side effects). 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