Late-onset Alzheimer disease risk variants mark brain regulatory loci
Open accessAbstract
OBJECTIVE: To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation. METHODS: Expression levels from the cerebellum (CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WG-DASL) for ∼400 autopsied patients (∼200 with AD and ∼200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within ±100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis-SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq). RESULTS: We identified strong associations of brain CR1, HLA-DRB1, and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis-SNPs for LOAD candidate genes MEF2C, ZCWPW1, and SLC24A4. MEF2C and SLC24A4, but not ZCWPW1 cis-SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1, HLA-DRB1, ZCWPW1, and SLC24A4. CONCLUSIONS: Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several 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 [202]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Self-citationHarold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · see citing works
Self-citationNaj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
Self-citationGenetic variability in the regulation of gene expression in ten regions of the human brain
UK Brain Expression Consortium, Ramasamy, A., North American Brain Expression Consortium, Trabzuni, D., Guelfi, S., Varghese, V., Smith, C., Walker, R., De, T., Coin, L., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3801 · Cited by 644 · see citing works
Brouwers, N., Van Cauwenberghe, C., Engelborghs, S., Lambert, J.-C., Bettens, K., Le Bastard, N., Pasquier, F., Montoya, A. G., Peeters, K., Mattheijssens, M., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.24 · Cited by 227 · see citing works
Replication of CLU, CR1, and PICALM Associations With Alzheimer Disease
Carrasquillo, M. M., Belbin, O., Hunter, T. A., Ma, L., Bisceglio, G. D., Zou, F., Crook, J. E., Pankratz, V. S., Dickson, D. W., Graff-Radford, N. R., et al. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.147 · Cited by 208 · see citing works
Self-citationBlockage of CR1 prevents activation of rodent microglia
Crehan, H., Hardy, J., & Pocock, J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.02.003 · Cited by 98 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease.
Forner, S., Kawauchi, S., Balderrama-Gutierrez, G., Kramár, E. A., Matheos, D. P., Phan, J., Javonillo, D. I., Tran, K. M., Hingco, E., da Cunha, C., et al. (2021) · Scientific Data · doi:10.1038/s41597-021-01054-y · Cited by 501 · see citing works
Genes associated with Alzheimer's disease: an overview and current status
Giri, M., Lü, Y., & Zhang, M. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s105769 · Cited by 311 · see citing works
Fang, J., Zhang, P., Wang, Q., Chiang, C.-W., Zhou, Y., Hou, Y., Xu, J., Chen, R., Zhang, B., Lewis, S. J., et al. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00951-z · Cited by 140 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“Several studies have performed targeted analysis of the impact of identified AD SNPs on brain-specific gene expression (Karch et al., 2016; Katsumata et al., 2019; Allen et al., 2015).”
BackgroundConway, O. J., Carrasquillo, M. M., Wang, X., Bredenberg, J. M., Reddy, J. S., Strickland, S. L., Younkin, C. S., Burgess, J. D., Allen, M., Lincoln, S. J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0289-x · Cited by 112 · see citing works
Self-citationSteele, N. Z. R., Carr, J. S., Bonham, L. W., Geier, E. G., Damotte, V., Miller, Z. A., Desikan, R. S., Boehme, K. L., Mukherjee, S., Crane, P. K., et al. (2017) · PLOS Medicine · doi:10.1371/journal.pmed.1002272 · Cited by 91 · see citing works
The immunogenetics of neurological disease
Misra, M. K., Damotte, V., & Hollenbach, J. A. (2018) · Immunology · doi:10.1111/imm.12869 · Cited by 74 · see citing works
Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping
Kikuchi, M., Hara, N., Hasegawa, M., Miyashita, A., Kuwano, R., Ikeuchi, T., & Nakaya, A. (2019) · BMC Medical Genomics · doi:10.1186/s12920-019-0574-8 · Cited by 74 · see citing works
“pression levels [15, 52]; however, it is not known how”
BackgroundResultInitiative, A. D. N., Tan, M.-S., Yang, Y.-X., Xu, W., Wang, H.-F., Tan, L., Zuo, C.-T., Dong, Q., Tan, L., Suckling, J., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00755-7 · Cited by 71 · see citing works
Liu, G., Wang, T., Tian, R., Hu, Y., Han, Z., Wang, P., Zhou, W., Ren, P., Zong, J., Jin, S., et al. (2018) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1144-9 · Cited by 20 · see citing works
- Authors
- Allen, M., Kachadoorian, M., Carrasquillo, M. M., Karhade, A., Manly, L., Burgess, J. D., Wang, C., Serie, D., Wang, X., Siuda, J., Zou, F., Chai, H. S., Younkin, C., Crook, J., Medway, C., Nguyen, T., Ma, L., Malphrus, K., Lincoln, S., Petersen, R. C., Graff-Radford, N. R., Asmann, Y. W., Dickson, D. W., Younkin, S. G., & Ertekin-Taner, N.
- Affiliations
- Mayo Clinic (US)
- From the Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
- ORCID
- Venue
- Neurology Genetics
- Published
- 2015-08
- Volume
- 1
- Issue
- 2
- Pages
- e15-e15
- ISSN
- 2376-7839 (ISSN-L)
- PMC
- PMC4807909
- OpenAlex
- W1885735168
- Cited by
- 73
- References
- 8
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 10 · 2021: 12 · 2020: 7 · 2019: 7 · 2018: 10 · 2017: 7 · 2016: 4
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Neurology Genetics (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (U01 AG016976, U01 AG032984, U24AG021886, AG033193)
- Wellcome Trust (082604/2/07/Z, 082604)
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Université de Lille
- Institut National de la Santé et de la Recherche Médicale
- Bundesministerium für Bildung und Forschung (01GI0102, 01GI0711, 01GI0420)
- Erasmus Medisch Centrum
- Hjartavernd (N01-AG-1-2100)
- Centre hospitalier régional universitaire de Lille
- National Institutes of Health (n01ag12100-57-0-2, N01-AG-1-2100, NIA AG081220, AG016976, AG021886)
- Medical Research Council (503480)
- National Institute on Aging (AG 016976, N01-AG12100, N01-AG012100, AG081220, U01AG016976, NIA AG081220, U01AG032984, AG033193, AG032984, U01AG046139, R01AG033193, AG021886, U24AG021886)
- National Heart, Lung, and Blood Institute (HL-105756, R01HL105756, AG033193)
- National Institute of Neurological Disorders and Stroke (R01NS080820)
- 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, brain gene expression, regulatory loci, complement receptor 1, HLA-DRB1, MEF2C, SLC24A4, temporal cortex, cerebellum, gene expression regulation
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 ›
Are you an author, or do you see a problem with this page? Request a review
