Alzheimer’s disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci
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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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rs199533 was significantly associated with MAPT and other transcripts in the MAPT region, including KIAA1267, LOC1, C17orf58, and LOC100294337.
“we found that rs199533 was significantly associated with MAPT (p=2 × 10−12) and a number of other transcripts in the MAPT region including KIAA1267 (p = 2.4 × 10−24), LOC1 (p = 1.1 × 10−23), C17orf58 (p=2.1 × 10-6) and LOC100294337 (p=2.2 × 10−6).”
From Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia (2017) · cites this paper as [23]
The Results sections on IGAP GWAS loci and eQTLs report associations for other SNPs and genes, but do not address rs199533 or its association with MAPT-region transcripts. Searches for rs199533 and MAPT found no passage supporting the named transcripts or p-values in our copy; absence of that finding is not a contradiction. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSeveral studies have performed targeted analysis of the impact of identified AD SNPs on brain-specific gene expression.
“Several studies have performed targeted analysis of the impact of identified AD SNPs on brain-specific gene expression [200–202].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [200]
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- Authors
- Karch, C. M., Ezerskiy, L. A., Bertelsen, S., Alzheimer’s Disease Genetics Consortium (ADGC), & Goate, A. M.
- Affiliations
- Washington University in St. Louis (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Karch, Celeste M.
- Goate, Alison M.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-02-26
- Volume
- 11
- Issue
- 2
- Pages
- e0148717
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4769299
- OpenAlex
- W2291645046
- Cited by
- 111
- References
- 40
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 12 · 2022: 14 · 2021: 17 · 2020: 11 · 2019: 11 · 2018: 12 · 2017: 13 · 2016: 2
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- National University of Singapore (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (U01 AG024904, P50 AG005138, AG024904)
- Howard Hughes Medical Institute
- Alzheimer's Association (P30 AG013854, P30AG010124, P50 AG023501, R01 AG17917, U01 AG016976, AG010129, AG05144, U01 AG032984, P50 AG005681, R01 AG30146, P30 AG010161, R01 AG15819, U01 AG024904, P30 AG010129, ADGC-10–196728, U24AG021886, P50 AG008702, AG033193, P50 AG005136, W81XWH-12-2-0012, P50 AG005146, R01 AG019085)
- Massachusetts General Hospital (P50 AG005134, HL105756)
- University of Southern California (P50AG005142, R01 AG15819, W81XWH-12-2-0012, U01 AG024904)
- Vanderbilt University (R01 AG019085)
- University of Miami (AG010491, R01 AG025259, AG019757, R01 AG019085, AG027944, AG021547, R01 AG027944)
- University of Pennsylvania (AG010124, P30 AG010124, U24‐AG041689, R01AG041797, U24 AG026395)
- Emory University (AG025688, P50 AG016573)
- Northwestern University (P30 AG013854)
- University of Washington (P50-AG005136, P50 AG005681, P01 AG03991, P50 AG033514)
- Johns Hopkins University (P50-AG005146, AG020688, R01 AG020688, AG005146, P50 AG016574)
- University of Pittsburgh (AG02365, AG07562, P50 AG005133, AG030653, AG041718)
- Rush University (P30 AG010161, R01 AG17917, AG17917, R01 AG15819, R01AG30146, R01 AG019085, AG30146)
- Wellcome Trust (082604/2/07/Z, 082604)
- Hope Center for Neurological Disorders
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Université de Lille
- Alzheimer's Research Trust (503176)
- York University
- Newcastle University
- Institut National de la Santé et de la Recherche Médicale
- Bundesministerium für Bildung und Forschung (01GI0102, 01GI0711, 01GI0420)
- Stichting MS Research
- Erasmus Medisch Centrum
- North Bristol NHS Trust
- Universitat de Barcelona
- Hersenstichting
- Hjartavernd (N01-AG-1-2100)
- Centre hospitalier régional universitaire de Lille (503480, 503176, 082604/2/07/Z)
- National Institutes of Health (AG081220, 5rc2ag036502-02, AG028 383, n01ag12100-57-0-2, N01-AG-1-2100, 5r01ag027944-05, 5u01ag024904-10, W81XWH-12-2-0012, DP1OD006849, 7r01ag019757-06, AG02365, 5r37ag015473-15, NIA AG081220, AG016574, AG016573, AG016976, AG010124, AG05144, AG023501, AG010491, 1RC2AG036502, U01-AG024904, AG019724, AG05128, AG005138, AG005133, Grant U01 AG024904, RR029893, P30 AG08051, AG005131, R01 AG027944, AG008017, AG010129, AG024904, AG005681, AG019757, AG019610, R37 AG015473, MH60451, U01 AG10483, AG005134, AG010161, AG013854, AG025688, AG10483, AG 03991, AG013846, AG15819, AG005136, AG027944, AG033514, AG008702, AG08051, UL1TR001445)
- University of California, Los Angeles (P50 AG016570)
- University of California, Davis (P30AG010129, AG033193, AG010129)
- University of California, San Diego (P50-AG005131, P50 AG005133)
- University of California, San Francisco (AG019724, P50 AG023501, P01AG019724)
- University of California, Irvine (P50AG016573)
- Canadian Institutes of Health Research
- Medical Research Council (503480, U01 AG024904, P30 AG010129)
- National Institute on Aging (AG006781, U01-AG-024904, AG 005138, R01AG017917, AG 10483, AG-028383, P01AG010491, AG 016976, AG-016570, AG 10133, AG05 128, AG026916, P30AG010129, P30AG010133, R01AG019085, AG-15819, AG017173, P30 AG 08051, AG-016573, P50AG005144, AG008702, U01‐AG10483, R01AG33193, R01AG030146, AG005134, AG021547, R01 AG30146, AG03991, W81XWH-12-2–0012, AG010491, R01‐AG17917, AG016582, N01-AG12100, AG-010124, AG-05144, P30AG028383, R01 AG15819, P30AG012300, AG 07562, R01AG041718, AG-005133, AG 025688, AG-005136, AG-17917, AG016574, AG008017, P50AG005133, R01-AG027944, U24-AG041689-01, AG 024904, AG081220, K01AG046374, P30AG028377, U01AG006781, U01AG016976, AG-005146, P50AG005131, R01-AG019757, AG-013854, NIA AG081220, R37-AG015473, P50AG005138, AG041718, R01AG022374, P50AG016570, AG019610, AG-005142, AG010161, AG036528, AG041689, R01AG007562, P50AG005128, P30AG010124, P50AG016573, AG019757, R01AG021547, R01AG041232, AG010129, R01AG030653, AG21886, U01AG010483, R01AG015819, P30AG008017, AG-033514, P30AG010161, AG005131, R01AG035083, AG031581, AG019085, U01AG032984, AG028377, AG015473, U24 AG21886, AG033193, R01AG012101, AG025259, CA129769, R01AG031581, P30AG008051, R01AG041797, AG046374, RC2-AG036502, P50AG016582, P50AG008702, AG 08051, AG02365, P50AG033514, AG023501, AG032984, AG013846, P50AG005681, P50AG005142, AG002219, P50AG008671, P30AG019610, R01AG026916, P50AG005146, P01 AG0 3991, P01AG003991, AG035083, AG019724, UO1 AG006781, 1RC2AG036502, AG049508, U24AG026395, P30AG013846, P50AG005136, P50AG005134, P30AG013854, R01AG025259, P50AG025688, AG026395, R01AG017173, RC2AG036528, U01AG049508, R01AG033193, P01AG002219, AG021886, R01AG013616, P30 AG-10133, AG005681, P01AG019724, U24AG041689, U24AG021886, P50AG023501, AG027944, R01AG020688, AG 030653, P50AG016574, R01AG035137, AG041232)
- National Heart, Lung, and Blood Institute (HL-105756, R01HL105756, AG033193, AG010129)
- National Institute of Mental Health (U01 AG024904, MH60451, R01MH080295, W81XWH-12-2-0012, 01GI0711, 082604/2/07/Z, NIA AG081220, 01GI0102, 503176, 01GI0420, P50MH060451)
- National Human Genome Research Institute (U01HG004610, U01HG006375)
- National Cancer Institute (R01CA129769, U54CA137788, U54CA132378)
- National Institute of Neurological Disorders and Stroke (NS3 9764, R01NS059873, AG033193, NS059873, MH60451, NIMH MH60451, P50NS039764, U24 AG21886)
- National Center for Research Resources (UL1RR029893)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- late-onset Alzheimer's disease, expression quantitative trait loci, single nucleotide polymorphisms, gene expression regulation, General Agreement on Trade in Services, MTCH2, microglia, neuroinflammation, brain gene expression
- MeSH terms
- CELF1 Protein, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Gene Expression Regulation, Humans, Male, Membrane Glycoproteins, Middle Aged, Receptors, Immunologic, Risk Factors, Linkage Disequilibrium, Case-Control Studies, Zinc Fingers, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Databases, Genetic, Mitochondrial Membrane Transport Proteins, Quantitative Trait Loci, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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