The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer’s disease susceptibility
Open accessAbstract
We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444(C), results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444(C), is associated with greater cell surface expression of CD33 in both subjects of European and African-American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r(2) > 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14(+)CD16(-) monocytes from 398 healthy subjects of three populations, we show that the rs3865444(C) risk allele is strongly associated with greater expression of CD33 exon 2 (pMETA = 2.36 × 10(-60)). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444(C) allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility.
Overview
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
Verification
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?
The cited source says what the claim attributes to it.
In the citing paper
“In addition, it is becoming increasingly clear that genetic risk can also be mediated through mRNA splicing28,29.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [29]
The cited source says what the claim attributes to it.
In the citing paper
“For instance, the CD33 locus in AD influences CD33 splicing, resulting in isoforms with different biological and likely pathological functions29.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [29]
In the citing paper
“The protective SNP alters CD33 mRNA splicing such that the extracellular sialic acid–binding domain is lost from the final protein (Malik et al., 2013, 2015; Raj et al., 2014).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Raj et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Browning, S. R., & Browning, B. L. (2007) · The American Journal of Human Genetics · doi:10.1086/521987 · Cited by 3,217
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
LocusZoom: regional visualization of genome-wide association scan results
Pruim, R. J., Welch, R. P., Sanna, S., Teslovich, T. M., Chines, P. S., Gliedt, T. P., Boehnke, M., Abecasis, G. R., & Willer, C. J. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq419 · Cited by 2,707
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
Siglecs and their roles in the immune system
Crocker, P. R., Paulson, J. C., & Varki, A. P. (2007) · Nature reviews. Immunology · doi:10.1038/nri2056 · Cited by 2,032
Initiative, T. A. D. N., Hollingworth, P., CHARGE consortium, EADI1 consortium, Harold, D., Sims, R., Gerrish, A., Lambert, J.-C., Carrasquillo, M. M., Abraham, R., et al. (2011) · Nature Genetics · doi:10.1038/ng.803 · Cited by 1,997
Naj, 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
Self-citationIntegrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease
Zhang, B., Gaiteri, C., Bodea, L.-G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., Zhang, C., Xie, T., Tran, L., Dobrin, R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.030 · Cited by 1,657
Self-citationBouchon, A., Dietrich, J., & Colonna, M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.10.4991 · Cited by 1,284 · cited 6×
“Our exon-level analysis of CD33 expression highlights an emerging role for an infiltrating macrophage and/or microglial activation network (including the genes TYROBP, CD33 and TREM2) in modulating AD susceptibility and pathology.”
BackgroundInfluentialAlzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
Griciuc, A., Serrano-Pozo, A., Parrado, A. R., Lesinski, A. N., Asselin, C. N., Mullin, K., Hooli, B., Choi, S. H., Hyman, B. T., & Tanzi, R. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.014 · Cited by 1,004
Overview and Findings from the Rush Memory and Aging Project
Bennett, D. A., Schneider, J. A., Buchman, A. S., Barnes, L. L., Boyle, P. A., & Wilson, R. S. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322663 · Cited by 849
Han, B., & Eskin, E. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.04.014 · Cited by 680
Overview and Findings from the Religious Orders Study
Bennett, D. A., Schneider, J. A., Arvanitakis, Z., & Wilson, R. S. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322573 · Cited by 656
CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology
Initiative, T. A. D. N., Bradshaw, E. M., Chibnik, L. B., Keenan, B. T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L. L., Imboywa, S., Lee, M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3435 · Cited by 570
Self-citationBertram, L., Lange, C., Mullin, K., Parkinson, M., Hsiao, M., Hogan, M. F., Schjeide, B. M. M., Hooli, B., DiVito, J., Ionita, I., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.10.008 · Cited by 511
Nica, A. C., Montgomery, S. B., Dimas, A. S., Stranger, B. E., Beazley, C., Barroso, I., & Dermitzakis, E. T. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000895 · Cited by 435
Reitz, C., Jun, G., Naj, A., Rajbhandary, R., Vardarajan, B. N., Wang, L.-S., Valladares, O., Lin, C.-F., Larson, E. B., Graff-Radford, N. R., et al. (2013) · JAMA · doi:10.1001/jama.2013.2973 · Cited by 431
Self-citationGenomewide Analysis of mRNA Processing in Yeast Using Splicing-Specific Microarrays
Clark, T. A., Sugnet, C. W., & Ares, M. (2002) · Science · doi:10.1126/science.1069415 · Cited by 411
CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing
Malik, M., Simpson, J. F., Parikh, I., Wilfred, B. R., Fardo, D. W., Nelson, P. T., & Estus, S. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1224-13.2013 · Cited by 262
A Comprehensive Genetic Association Study of Alzheimer Disease in African Americans
Logue, M. W. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.646 · Cited by 250
Genome-wide association study of Alzheimer's disease
Kamboh, M. I., Demirci, F. Y., Wang, X., Minster, R. L., Carrasquillo, M. M., Pankratz, V. S., Younkin, S. G., Saykin, A. J., Initiative, A. D. N., Jun, G., et al. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.45 · Cited by 242
Hernández‐Caselles, T., Martinez‐Esparza, M., Pérez‐Oliva, A. B., Quintanilla-Cecconi, A. M., García-Alonso, A. M., Álvarez‐López, D. M. R., & García–Peñarrubia, P. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0205096 · Cited by 133
Identification of cis-regulatory variation influencing protein abundance levels in human plasma
Lourdusamy, A., Newhouse, S., Lunnon, K., Proitsi, P., Powell, J. F., Hodges, A., Nelson, S. K., Stewart, A., Williams, S. A., Kłoszewska, I., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds186 · Cited by 86
Carrasquillo, M. M., Belbin, O., Hunter, T. A., Ma, L., Bisceglio, G. D., Zou, F., Crook, J. E., Pankratz, V. S., Sando, S. B., Aasly, J. O., et al. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-54 · Cited by 82
Association of GWAS Top Hits With Late-onset Alzheimer Disease in Korean Population
Chung, S. J., Lee, J., Kim, S. Y., You, S., Kim, M. J., Lee, J., & Koh, J. (2012) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31826d7281 · Cited by 74
Microglia as Dynamic and Essential Components of the Amyloid Hypothesis
Gandy, S., & Heppner, F. L. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.007 · Cited by 74
The prevalence of CD33 and MS4A6A variant in Chinese Han population with Alzheimer’s disease
Deng, Y., Liu, L., Wang, Y., Tang, H., Ren, R., Xu, W. L., Ma, J., Wang, L., Zhuang, J.-P., Wang, G., et al. (2012) · Human Genetics · doi:10.1007/s00439-012-1154-6 · Cited by 54
Flagged first, then by citations
Research works printed but not linked: 1
- 2012, Alzheimer disease and associated disorders, 27, 250
Cited by
Sorted by citations
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
“A combined analysis of neuroimaging and genetic data found an association between a polymorphism in the IL1RAP gene and increased rate of Aβ accumulation in human brains of both AD and non-AD subjects (measured by Aβ-binding positron emission tomography tracer; Ramanan et al., 2015).”
BackgroundReligious Orders Study and Rush Memory and Aging Project
Bennett, D. A., Buchman, A. S., Boyle, P. A., Barnes, L. L., Wilson, R. S., & Schneider, J. A. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179939 · Cited by 1,260
Self-citationSiglec-mediated regulation of immune cell function in disease
Macauley, M. S., Crocker, P. R., & Paulson, J. C. (2014) · Nature Reviews Immunology · doi:10.1038/nri3737 · Cited by 1,122
Schwartzentruber, J., Cooper, S., Liu, J. Z., Barrio-Hernandez, I., Bello, E., Kumasaka, N., Young, A. M. H., Franklin, R. J. M., Johnson, T., Estrada, K., et al. (2021) · Nature Genetics · doi:10.1038/s41588-020-00776-w · Cited by 532
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532
Metadata
- Authors
- Raj, T., Ryan, K. J., Replogle, J. M., Chibnik, L. B., Rosenkrantz, L., Tang, A., Rothamel, K., Stranger, B. E., Bennett, D. A., Evans, D. A., De Jager, P. L., & Bradshaw, E. M.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- University of Chicago (US)
- Rush University Medical Center (US)
- Corresponding author
- Bradshaw, E. M.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-12-30
- Volume
- 23
- Issue
- 10
- Pages
- 2729-2736
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3990171
- OpenAlex
- W2161428211
- Cited by
- 144
- References
- 27
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 18 · 2021: 20 · 2020: 18 · 2019: 13 · 2018: 9 · 2017: 9 · 2016: 9 · 2015: 7 · 2014: 8
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG017917, P30-AG 10161, K25AG041906, R01AG030146, R01 AG30146, R01‐AG17917, R01 AG15819, R01AG11101, R01AG011101, R01AG043617, R01AG015819, P30AG010161, F32AG043267, R01AG031553)
- National Institute of General Medical Sciences (RC2GM093080)
- National Institute of Neurological Disorders and Stroke (R01NS067305)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- CD33, Alzheimer's disease, alternative splicing, exon 2, monocytes, cell surface expression, haplotypes, linkage disequilibrium, SRSF2, genetic susceptibility, CD14+CD16+ monocytes
- MeSH terms
- Alzheimer Disease, Black or African American, Exons, Humans, Linkage Disequilibrium, Case-Control Studies, Alternative Splicing, Sequence Analysis, DNA, Protein Structure, Tertiary, Genetic Predisposition to Disease, Protein Isoforms, Polymorphism, Single Nucleotide, White People, Genetic Association Studies, Sialic Acid Binding Ig-like Lectin 3
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
