Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation

dc.contributor.authorPugalenthi, Pradeep Varathan
dc.contributor.authorHe, Bing
dc.contributor.authorXie, Linhui
dc.contributor.authorNho, Kwangsik
dc.contributor.authorSaykin, Andrew J.
dc.contributor.authorYan, Jingwen
dc.contributor.departmentBiomedical Engineering and Informatics, Luddy School of Informatics, Computing, and Engineering
dc.date.accessioned2024-12-05T12:39:22Z
dc.date.available2024-12-05T12:39:22Z
dc.date.issued2024-11-13
dc.description.abstractAlzheimer'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 set of SNPs significantly 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 around APOE region 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.
dc.eprint.versionFinal published version
dc.identifier.citationPugalenthi PV, He B, Xie L, Nho K, Saykin AJ, Yan J. Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation. BioData Min. 2024;17(1):50. Published 2024 Nov 13. doi:10.1186/s13040-024-00400-1
dc.identifier.urihttps://hdl.handle.net/1805/44769
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1186/s13040-024-00400-1
dc.relation.journalBioData Mining
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.sourcePMC
dc.subjectAlzheimer’s disease
dc.subjectChromatin feature
dc.subjectGWAS annotation
dc.titleDeciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation
dc.typeArticle
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