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Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants.

TitleSet-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants.
Publication TypeJournal Article
Year of Publication2021
AuthorsPatel D, Zhang X, Farrell JJ, Lunetta KL, Farrer LA
JournalGenes (Basel)
Volume12
Issue3
Date Published2021 03 15
ISSN2073-4425
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Gene Expression, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Immune System, Inflammation, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Signal Transduction
Abstract

Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer's Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes and . In the blood, 307 genes were significant targets for rare eSNPs. In the blood and the brain, , , , , and were targets for significant eSNPs. Pathway enrichment analysis revealed significant pathways in the brain ( = 9) and blood ( = 16). Pathways for apoptosis signaling, cholecystokinin receptor (CCKR) signaling, and inflammation mediated by chemokine and cytokine signaling were common to both tissues. Significant rare eQTLs in inflammation pathways included five genes in the blood (, , , , ) that were previously linked to AD. This study identified several significant gene- and pathway-level rare eQTLs, which further confirmed the importance of the immune system and inflammation in AD and highlighted the advantages of using a set-based eQTL approach for evaluating the effect of low-frequency and rare variants on gene expression.

DOI10.3390/genes12030419
Pubmed Linkhttps://www.ncbi.nlm.nih.gov/pubmed/33804025?dopt=Abstract
page_expoInternal
Alternate JournalGenes (Basel)
PubMed ID33804025
PubMed Central IDPMC7999141
Grant ListRF1-AG057519 / AG / NIA NIH HHS / United States
2R01-AG048927 / AG / NIA NIH HHS / United States
U01-AG058654 / AG / NIA NIH HHS / United States
P30-AG13846 / AG / NIA NIH HHS / United States
3U01-AG032984 / AG / NIA NIH HHS / United States
U01-AG062602 / AG / NIA NIH HHS / United States
U19-AG068753 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
/ / CIHR / Canada

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