A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits

A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex 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 Article A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits Xiaofeng Zhu, Yihe Yang, Noah Lorincz-Comi, Gen Li, Amy Bentley, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3338723/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Apr, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the CHARGE Gene-Lifestyle Interactions Working Group has been spearheading efforts to investigate G X E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identified and confirmed 5 loci (6 independent signals) interacting with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrated that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated contribution ranges from 1.76–14.05% of SNP heritability of serum lipids in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits. Biological sciences/Genetics/Genetic association study Health sciences/Risk factors Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTablesV18.xlsx SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 22 Apr, 2024 Read the published version in Nature Communications → 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3338723","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":237921748,"identity":"6f6f847f-c1e9-4663-bc5f-0b16f29333fd","order_by":0,"name":"Xiaofeng Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYJCCAwkVUBYPkToYD3w4Q6IW5oMz20jRYnAj/cFh3nl28vLtDYwP3rYR1sEg2XMg4TDvtmTDDWcOMBvOJUYLP3vDAaCWA4wbJBLYpHmJ0cLGzNhwmHfOAfv58x+w/yZKCz97M8PBmQ0HEhtuALUTpUWy5xjDgQ/HkpM3nElslpxzjggtwBB7/CGhxs52fvvhgx/elBGhBQkwNpCmfhSMglEwCkYBbgAAkQk5bExgjE0AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-0037-411X","institution":"Case Western Reserve University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xiaofeng","middleName":"","lastName":"Zhu","suffix":""},{"id":237921749,"identity":"bb406281-cfb7-43ed-9352-93637f7a1122","order_by":1,"name":"Yihe Yang","email":"","orcid":"https://orcid.org/0000-0001-6563-3579","institution":"Case Western Reserve University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yihe","middleName":"","lastName":"Yang","suffix":""},{"id":237921750,"identity":"b4a91c87-94b6-4aac-848d-9002d6c77844","order_by":2,"name":"Noah Lorincz-Comi","email":"","orcid":"https://orcid.org/0000-0002-0517-2499","institution":"Case Western Reserve University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noah","middleName":"","lastName":"Lorincz-Comi","suffix":""},{"id":237921751,"identity":"04da5e3b-2ba1-471d-ae06-3d25aff4a576","order_by":3,"name":"Gen Li","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gen","middleName":"","lastName":"Li","suffix":""},{"id":237921752,"identity":"f49da4d3-5329-4110-8c91-d12a2f264d63","order_by":4,"name":"Amy Bentley","email":"","orcid":"https://orcid.org/0000-0002-0827-9101","institution":"National Institutes of Health, NHGRI","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amy","middleName":"","lastName":"Bentley","suffix":""},{"id":237921753,"identity":"39fea580-c531-40ce-8c04-3c78c1419902","order_by":5,"name":"Paul de Vries","email":"","orcid":"","institution":"Human Genetics Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"de Vries","suffix":""},{"id":237921754,"identity":"8a1bc6c0-990a-4756-b093-c096eee63460","order_by":6,"name":"Michael Brown","email":"","orcid":"","institution":"University of Texas","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Brown","suffix":""},{"id":237921755,"identity":"5fbf12c7-b2ea-4998-b712-4a10fc642087","order_by":7,"name":"Alanna Morrison","email":"","orcid":"https://orcid.org/0000-0001-6381-4296","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alanna","middleName":"","lastName":"Morrison","suffix":""},{"id":237921756,"identity":"48966e0a-71b1-428d-a157-84dfc9691552","order_by":8,"name":"Charles Rotimi","email":"","orcid":"https://orcid.org/0000-0001-5759-053X","institution":"National Institutes of health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Charles","middleName":"","lastName":"Rotimi","suffix":""},{"id":237921757,"identity":"e73793d6-d6a2-48d0-b128-3e60515fa937","order_by":9,"name":"W. 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