Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci.

TitleAlzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci.
Publication TypeJournal Article
Year of Publication2016
AuthorsKarch, CM, Ezerskiy, LA, Bertelsen, S, Goate, AM
Corporate AuthorsAlzheimer’s Disease Genetics Consortium (ADGC)
JournalPLoS One
Volume11
Issue2
Paginatione0148717
Date Published2016
ISSN1932-6203
KeywordsAge of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Case-Control Studies, CELF1 Protein, Databases, Genetic, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Membrane Glycoproteins, Middle Aged, Mitochondrial Membrane Transport Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Immunologic, Risk Factors, Zinc Fingers
Abstract

Late onset Alzheimer's disease (LOAD) is a genetically complex and clinically heterogeneous disease. Recent large-scale genome wide association studies (GWAS) have identified more than twenty loci that modify risk for AD. Despite the identification of these loci, little progress has been made in identifying the functional variants that explain the association with AD risk. Thus, we sought to determine whether the novel LOAD GWAS single nucleotide polymorphisms (SNPs) alter expression of LOAD GWAS genes and whether expression of these genes is altered in AD brains. The majority of LOAD GWAS SNPs occur in gene dense regions under large linkage disequilibrium (LD) blocks, making it unclear which gene(s) are modified by the SNP. Thus, we tested for brain expression quantitative trait loci (eQTLs) between LOAD GWAS SNPs and SNPs in high LD with the LOAD GWAS SNPs in all of the genes within the GWAS loci. We found a significant eQTL between rs1476679 and PILRB and GATS, which occurs within the ZCWPW1 locus. PILRB and GATS expression levels, within the ZCWPW1 locus, were also associated with AD status. Rs7120548 was associated with MTCH2 expression, which occurs within the CELF1 locus. Additionally, expression of several genes within the CELF1 locus, including MTCH2, were highly correlated with one another and were associated with AD status. We further demonstrate that PILRB, as well as other genes within the GWAS loci, are most highly expressed in microglia. These findings together with the function of PILRB as a DAP12 receptor supports the critical role of microglia and neuroinflammation in AD risk.

DOI10.1371/journal.pone.0148717
Alternate JournalPLoS ONE
PubMed ID26919393
PubMed Central IDPMC4769299
Grant ListP30 AG013854 / AG / NIA NIH HHS / United States
P50 MH060451 / MH / NIMH NIH HHS / United States
082604/2/07/Z / / Wellcome Trust / United Kingdom
MH60451 / MH / NIMH NIH HHS / United States
UL1 TR001445 / TR / NCATS NIH HHS / United States
R01 AG022374 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
AG041232 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
503480 / / Medical Research Council / United Kingdom
AG07562 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
R01 AG035137 / AG / NIA NIH HHS / United States
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AG02365 / AG / NIA NIH HHS / United States
AG049508 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
AG05128 / AG / NIA NIH HHS / United States
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