Alzheimer's disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci

Alzheimer's Disease Genetics Consortium (ADGC)

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0148717
JournalPLoS One
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2016

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Genome-Wide Association Study
Alzheimer disease
Polymorphism
Gene expression
Alzheimer Disease
Genes
genetic polymorphism
single nucleotide polymorphism
Single Nucleotide Polymorphism
Gene Expression
gene expression
loci
Nucleotides
Quantitative Trait Loci
Linkage Disequilibrium
neuroglia
Microglia
linkage disequilibrium
genes
quantitative trait loci

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Alzheimer's disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci. / Alzheimer's Disease Genetics Consortium (ADGC).

In: PLoS One, Vol. 11, No. 2, e0148717, 01.02.2016.

Research output: Contribution to journalArticle

Alzheimer's Disease Genetics Consortium (ADGC). / Alzheimer's disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci. In: PLoS One. 2016 ; Vol. 11, No. 2.
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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.",
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AU - Bertelsen, Sarah

AU - Goate, Alison M.

AU - Albert, Marilyn S.

AU - Albin, Roger L.

AU - Apostolova, Liana G.

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AU - Bird, Thomas D.

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AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Buxbaum, Joseph D.

AU - Cairns, Nigel J.

AU - Cantwell, Laura B.

AU - Cao, Chuanhai

AU - Carlson, Chris S.

AU - Carney, Regina M.

AU - Carrasquillo, Minerva M.

AU - Carroll, Steven L.

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AU - Dick, Malcolm

AU - Dickson, Dennis W.

AU - Duara, Ranjan

AU - Ertekin-Taner, Nilufer

AU - Kaye, Jeffrey

AU - Pierce, Aimee

AU - Quinn, Joseph

AU - Woltjer, Randall (Randy)

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