{"paper_id":"bd0a8b26-8428-4089-8d8e-c2f18288d988","body_text":"Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation | 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 Research Article Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation Pradeep Varathan Pugalenthi, Bing He, Linhui Xie, Kwangsik Nho, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3871665/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Nov, 2024 Read the published version in BioData Mining → Version 1 posted 9 You are reading this latest preprint version Abstract Alzheimer’s disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks and the need for reanalysis of GWAS findings as clusters. Alzheimer’s disease GWAS annotation chromatin feature Full Text Additional Declarations No competing interests reported. Supplementary Files supplementeryfigure1.png AppendixA.csv Appendix A Top AD GWAS SNPs Top 100 AD GWAS SNPs included in this study are listed in Appendix A.csv. AppendixB.csv Appendix B Brain related chromatin features in Expecto Brain-related chromatin features related to brain were manually extracted from Expecto, and are listed in Appendix B.csv Cite Share Download PDF Status: Published Journal Publication published 13 Nov, 2024 Read the published version in BioData Mining → Version 1 posted Editorial decision: Revision requested 18 Jun, 2024 Reviews received at journal 19 May, 2024 Reviewers agreed at journal 11 May, 2024 Reviews received at journal 07 May, 2024 Reviewers agreed at journal 24 Apr, 2024 Reviewers invited by journal 23 Apr, 2024 Editor assigned by journal 07 Feb, 2024 Submission checks completed at journal 06 Feb, 2024 First submitted to journal 16 Jan, 2024 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-3871665\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":271596831,\"identity\":\"f8f34435-f352-4351-b3ba-0b0283a540c7\",\"order_by\":0,\"name\":\"Pradeep Varathan Pugalenthi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Indiana University – Purdue University 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Large-scale genome-wide association studies (GWASs) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. 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