Translating Alzheimer's Disease-associated Polymorphisms into Functional Candidates: a Survey of IGAP Genes and SNPs.

TitleTranslating Alzheimer's Disease-associated Polymorphisms into Functional Candidates: a Survey of IGAP Genes and SNPs.
Publication TypeJournal Article
Year of Publication2019
AuthorsKatsumata Y, Nelson PT, Estus S, Fardo DW
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative(ADNI)
JournalNeurobiol Aging
Volume74
Pagination135-146
Date Published02/2019
ISSN1558-1497
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Carrier Proteins, CELF1 Protein, Desmoglein 2, Female, Genetic Association Studies, Humans, Linkage Disequilibrium, Male, Membrane Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA, Messenger, RNA, Untranslated, SAP90-PSD95 Associated Proteins, Transcription, Genetic
Abstract

The International Genomics of Alzheimer's Project (IGAP) is a consortium for characterizing the genetic landscape of Alzheimer's disease (AD). The identified and/or confirmed 19 single-nucleotide polymorphisms (SNPs) associated with AD are located on non-coding DNA regions, and their functional impacts on AD are as yet poorly understood. We evaluated the roles of the IGAP SNPs by integrating data from many resources, based on whether the IGAP SNP was (1) a proxy for a coding SNP or (2) associated with altered mRNA transcript levels. For (1), we confirmed that 12 AD-associated coding common SNPs and five nonsynonymous rare variants are in linkage disequilibrium with the IGAP SNPs. For (2), the IGAP SNPs in CELF1 and MS4A6A were associated with expression of their neighboring genes, MYBPC3 and MS4A6A, respectively, in blood. The IGAP SNP in DSG2 was an expression quantitative trait loci (eQTL) for DLGAP1 and NETO1 in the human frontal cortex. The IGAP SNPs in ABCA7, CD2AP, and CD33 each acted as eQTL for AD-associated genes in brain. Our approach for identifying proxies and examining eQTL highlighted potentially impactful, novel gene regulatory phenomena pertinent to the AD phenotype.

DOI10.1016/j.neurobiolaging.2018.10.017
Alternate JournalNeurobiol. Aging
PubMed ID30448613
PubMed Central IDPMC6331247
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