Determinants of pleiotropy and monotonic gene dosage responses across human traits

Determinants of pleiotropy and monotonic gene dosage responses across human traits | 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 Biological Sciences - Article Determinants of pleiotropy and monotonic gene dosage responses across human traits Sayeh Kazem, Kuldeep Kumar, Guillaume Huguet, Josephine Mollon, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7547111/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract While pleiotropic effects of gene dosage are of particular relevance for comorbidities observed in the developmental pediatric and psychiatric clinic, the biological processes underlying such pleiotropy remain unknown. We developed a new functional burden analysis (FunBurd) to investigate all CNVs, genome-wide, beyond well-studied recurrent CNVs. In ~500,000 UK-Biobank participants, we tested the association between 43 traits and CNVs disrupting 172 tissue or cell-type gene-sets. CNVs affected all traits. Pleiotropy was correlated with genetic constraint and was higher in the brain compared to non-brain functions, even after normalizing for genetic constraint. The levels of pleiotropy, measured by burden correlation, were similar in deletions and loss-of-function SNVs and higher compared to common variants and duplications. Gene sets under high genetic constraint showed less monotonic gene dosage responses across traits. Even in the absence of a monotonic response, we observed a negative correlation between deletion and duplication effect sizes across most traits. Overall, functional gene sets are preferentially associated with a given trait when either deleted or duplicated, but rarely both. Biological sciences/Genetics/Functional genomics Biological sciences/Genetics/Genetic association study Biological sciences/Molecular biology/Transcriptomics Health sciences/Risk factors Biological sciences/Genetics/Population genetics/Genetic variation/Rare variants Full Text Additional Declarations There is NO Competing Interest. The authors declare no competing interests. Supplementary Files SupplementalTablesST1toST12.xlsx SupplementalTables SupplementalFiguresS1toS26.pdf SupplementalFigures Cite Share Download PDF Status: Under Review 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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