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

Celeste M Karch; Lubov A Ezerskiy; Sarah Bertelsen; Alison M Goate

doi:10.1371/journal.pone.0148717

Back

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

Journal article

Open access

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

Celeste M Karch, Lubov A Ezerskiy, Sarah Bertelsen and Alison M Goate

PloS one, Vol.11(2), pp.e0148717-e0148717

2016

DOI: https://doi.org/10.1371/journal.pone.0148717

PMCID: PMC4769299

PMID: 26919393

Appears in UM Open Access Research Published in PloS

Abstract

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Middle Aged

Risk Factors

Gene Expression Regulation

Databases, Genetic

Male

Case-Control Studies

Linkage Disequilibrium

Membrane Glycoproteins - genetics

Mitochondrial Membrane Transport Proteins - genetics

Brain - metabolism

CELF1 Protein - genetics

Age of Onset

Alzheimer Disease - metabolism

Aged, 80 and over

Female

Zinc Fingers - genetics

Aged

Polymorphism, Single Nucleotide

Alzheimer Disease - genetics

Quantitative Trait Loci

Receptors, Immunologic - genetics

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.

Files and links (1)

url

https://doi.org/10.1371/journal.pone.0148717View

Published (Version of record) Open

Metrics

9 Record Views

72 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci
Creators: Celeste M Karch - Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, United States of America
Lubov A Ezerskiy - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Sarah Bertelsen - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States of America
Alison M Goate - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States of America
Publication Details: PloS one, Vol.11(2), pp.e0148717-e0148717
Publisher: United States
Grant note: P30 AG028377 / NIA NIH HHS P50 NS039764 / NINDS NIH HHS R01 AG027944 / NIA NIH HHS P50 AG005144 / NIA NIH HHS R01AG041797 / NIA NIH HHS R01 AG030146 / NIA NIH HHS P50 MH060451 / NIMH NIH HHS P50 AG008702 / NIA NIH HHS P50 AG023501 / NIA NIH HHS R37 AG015473 / NIA NIH HHS P01 AG010491 / NIA NIH HHS P50 AG005681 / NIA NIH HHS P30 AG008017 / NIA NIH HHS R01 AG031581 / NIA NIH HHS R01 AG019085 / NIA NIH HHS AG05144 / NIA NIH HHS 5R01AG012101 / NIA NIH HHS P01 AG03991 / NIA NIH HHS R01 AG030653 / NIA NIH HHS 5R01AG022374 / NIA NIH HHS R01 AG041797 / NIA NIH HHS R01 AG021547 / NIA NIH HHS P50 AG016573 / NIA NIH HHS P01 AG019724 / NIA NIH HHS N01-AG-12100 / NIA NIH HHS U24 AG21886 / NIA NIH HHS R01 MH080295 / NIMH NIH HHS P50 AG005134 / NIA NIH HHS P50 AG005128 / NIA NIH HHS AG041232 / NIA NIH HHS Wellcome Trust MH60451 / NIMH NIH HHS NS39764 / NINDS NIH HHS R01 CA129769 / NCI NIH HHS R01 AG035137 / NIA NIH HHS P30 AG08051 / NIA NIH HHS DP1 OD006849 / NIH HHS P30 AG010129 / NIA NIH HHS R01 AG020688 / NIA NIH HHS AG041718 / NIA NIH HHS R01 AG022374 / NIA NIH HHS R01 AG026916 / NIA NIH HHS P50 AG005142 / NIA NIH HHS R01 NS059873 / NINDS NIH HHS K01 AG046374 / NIA NIH HHS U24 AG026395 / NIA NIH HHS P30 AG010124 / NIA NIH HHS R01 AG17917 / NIA NIH HHS U01 AG016976 / NIA NIH HHS U24 AG021886 / NIA NIH HHS R01 AG017917 / NIA NIH HHS P30 AG008051 / NIA NIH HHS U01 AG032984 / NIA NIH HHS AG049508 / NIA NIH HHS U01 AG006781 / NIA NIH HHS P50 AG016574 / NIA NIH HHS P50 AG008671 / NIA NIH HHS R01 AG035083 / NIA NIH HHS R01 AG019757 / NIA NIH HHS R01 AG30146 / NIA NIH HHS RC2 AG036528 / NIA NIH HHS R01 AG041232 / NIA NIH HHS Howard Hughes Medical Institute R01 AG041718 / NIA NIH HHS P50 AG005131 / NIA NIH HHS P30 AG019610 / NIA NIH HHS P01 AG002219 / NIA NIH HHS UL1 TR001445 / NCATS NIH HHS P50 AG005136 / NIA NIH HHS U01 AG024904 / NIA NIH HHS AG035083 / NIA NIH HHS 1R01AG035137 / NIA NIH HHS R01AG33193 / NIA NIH HHS 5R01AG013616 / NIA NIH HHS AG021547 / NIA NIH HHS U01 HG006375 / NHGRI NIH HHS P50 AG005146 / NIA NIH HHS AG030653 / NIA NIH HHS P50 AG016582 / NIA NIH HHS U01 HG004610 / NHGRI NIH HHS P50 AG016570 / NIA NIH HHS P50 AG033514 / NIA NIH HHS AG046374 / NIA NIH HHS P30 AG010161 / NIA NIH HHS P30 AG013854 / NIA NIH HHS AG027944 / NIA NIH HHS U24 AG041689 / NIA NIH HHS R01 AG012101 / NIA NIH HHS R01 AG017173 / NIA NIH HHS U24-AG041689-01 / NIA NIH HHS R01 AG015819 / NIA NIH HHS P30 AG10133 / NIA NIH HHS 1RC2AG036502 / NIA NIH HHS U01 AG10483 / NIA NIH HHS AG05128 / NIA NIH HHS R01 AG033193 / NIA NIH HHS R01 AG15819 / NIA NIH HHS AG010491 / NIA NIH HHS AG019757 / NIA NIH HHS AG07562 / NIA NIH HHS U01 AG010483 / NIA NIH HHS 082604/2/07/Z / Wellcome Trust P30 AG028383 / NIA NIH HHS P30 AG012300 / NIA NIH HHS P30 AG010133 / NIA NIH HHS P50 AG005133 / NIA NIH HHS R01 AG013616 / NIA NIH HHS P50 AG025688 / NIA NIH HHS P01 AG003991 / NIA NIH HHS CIHR R01 AG025259 / NIA NIH HHS P30 AG013846 / NIA NIH HHS AG025688 / NIA NIH HHS R01 HL105756 / NHLBI NIH HHS P50 AG005138 / NIA NIH HHS AG02365 / NIA NIH HHS AG081220 / NIA NIH HHS U01 AG049508 / NIA NIH HHS 503480 / Medical Research Council UL1 RR029893 / NCRR NIH HHS RC2 AG036502 / NIA NIH HHS
Language: English
Resource Type: Journal article
PMID: 26919393
PMCID: PMC4769299
Record Identifier: 991031576636802976