Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease
Abstract
Several variants in the gene ABCA7 have been identified as potential causal variants for late-onset Alzheimer's disease (LOAD). In order to replicate these findings, and search for novel causal variants, we performed targeted sequencing of this gene in cohorts of non-Hispanic White (NHW) and African-American (AA) LOAD cases and controls. We sequenced the gene ABCA7 in 291 NHW LOAD cases and 103 controls. Variants were prioritized for rare, damaging variants and previously reported variants associated with LOAD, and were follow-up genotyped in 4076 NHW and 1157 AA cases and controls. We confirm three previously associated ABCA7 risk variants and extend two of these associations to other populations, an intronic variant in NHW (P=3.0×10-3) (originally reported in a Belgian population), and a splice variant originally associated in the Icelandic population, which was significantly associated in the NHW cohort (P=1.2×10-6) and nominally associated in the AA cohort (P=0.017). We also identify a 3'-UTR splice variant that segregates in four siblings of one family and is nominally associated with LOAD (P=0.040). Multiple variants in ABCA7 contribute to LOAD risk.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Using a large whole-exome-sequencing study, ten genes located in genome-wide loci were identified as having rare deleterious coding, splicing or LOF burden associations with LOAD (FDR P < 0.01), including ABCA7, TREM2, SORL1, TREML4, TAP2, PSMB8, PIP, STYX, RIN3, and KCNH6.
“we also identified ten genes located in our genome-wide loci as having rare deleterious coding, splicing or LOF burden associations with LOAD (false discovery rate (FDR) P < 0.01), including previously implicated rare-variant signals in ABCA7, TREM2, and SORL1 (refs. 14,49–55), and additional associations with TREML4 in the TREM2 locus, TAP2 and PSMB8 in the HLA-DRB1 locus, PIP in the EPHA1 locus,”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [53]
Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Kawas, C. H., Klunk, W. E., Koroshetz, W. J., Manly, J. J., Mayeux, R., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.005 · Cited by 18,657 · see citing works
A global reference for human genetic variation
The 1000 Genomes Project Consortium, authors, C., Auton, A., Abecasis, G. R., Steering committee, Altshuler, D. M., Durbin, R. M., Abecasis, G. R., Bentley, D. R., Chakravarti, A., et al. (2015) · Nature · doi:10.1038/nature15393 · Cited by 18,247 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · 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-citationAnnotation of functional variation in personal genomes using RegulomeDB
Boyle, A. P., Hong, E. L., Hariharan, M., Cheng, Y., Schaub, M. A., Kasowski, M., Karczewski, K. J., Park, J., Hitz, B. C., Weng, S., et al. (2012) · Genome Research · doi:10.1101/gr.137323.112 · Cited by 2,722 · see citing works
Rare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association Test
Wu, M. C., Lee, S., Cai, T., Li, Y., Boehnke, M., & Lin, X. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.05.029 · Cited by 2,317 · see citing works
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 · see citing works
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 · see citing works
Self-citationdbSNP: a database of single nucleotide polymorphisms
Smigielski, E. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.352 · Cited by 623 · see citing works
ApoE-4 and Age at Onset of Alzheimer's Disease: The NIMH Genetics Initiative
Blacker, D., Haines, J. L., Rodes, L., Terwedow, H., Go, R. C. P., Harrell, L. E., Perry, R. T., Bassett, S. S., Chase, G., Meyers, D., et al. (1997) · Neurology · doi:10.1212/wnl.48.1.139 · Cited by 479 · see citing works
Self-citationReitz, 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 · see citing works
Self-citationJun, G. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.201 · Cited by 422 · see citing works
Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease
DemGene, Steinberg, S., Stefansson, H., Jonsson, T., Johannsdottir, H., Ingason, A., Helgason, H., Sulem, P., Magnusson, O. T., Gudjonsson, S. A., et al. (2015) · Nature Genetics · doi:10.1038/ng.3246 · Cited by 324 · see citing works
Tau exon 10 alternative splicing and tauopathies
Liu, F., & Gong, C.-X. (2008) · Molecular Neurodegeneration · doi:10.1186/1750-1326-3-8 · Cited by 323 · see citing works
Yu, L., Chibnik, L. B., Srivastava, G. P., Pochet, N., Yang, J., Xu, J., Kozubek, J., Obholzer, N., Leurgans, S. E., Schneider, J. A., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3049 · Cited by 290 · see citing works
Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease
Beecham, G. W., Martin, E. R., Li, Y.-J., Slifer, M. A., Gilbert, J. R., Haines, J. L., & Pericak-Vance, M. A. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.12.008 · Cited by 260 · see citing works
Self-citationAnalysis of alternative splicing associated with aging and neurodegeneration in the human brain
Tollervey, J. R., Wang, Z., Hortobágyi, T., Witten, J. T., Zarnack, K., Kayikci, M., Clark, T. A., Schweitzer, A. C., Rot, G., Curk, T., et al. (2011) · Genome Research · doi:10.1101/gr.122226.111 · Cited by 252 · see citing works
Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology
Shulman, J. M., Chen, K., Keenan, B. T., Chibnik, L. B., Fleisher, A., Thiyyagura, P., Roontiva, A., Aubin, C., Patsopoulos, N. A., Corneveaux, J. J., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.2815 · Cited by 156 · see citing works
Cuyvers, E., De Roeck, A., Van den Bossche, T., Van Cauwenberghe, C., Bettens, K., Vermeulen, S., Mattheijssens, M., Peeters, K., Engelborghs, S., Vandenbulcke, M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00133-7 · Cited by 152 · see citing works
Vardarajan, B. N., Ghani, M., Kahn, A., Sheikh, S., Sato, C., Barral, S., Lee, J. H., Cheng, R., Reitz, C., Lantigua, R., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24466 · Cited by 148 · see citing works
ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology
Sakae, N., Liu, C., Shinohara, M., Frisch‐Daiello, J. L., Ma, L., Yamazaki, Y., Tachibana, M., Younkin, L. H., Kurti, A., Carrasquillo, M. M., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3757-15.2016 · Cited by 146 · see citing works
Beyer, K., & Ariza, A. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8330-5 · Cited by 134 · see citing works
Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study
Lee, J. H., Cheng, R., Graff-Radford, N., Foroud, T., & Mayeux, R. (2008) · Archives of Neurology · doi:10.1001/archneur.65.11.1518 · Cited by 132 · see citing works
ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing
Satoh, K., Abe-Dohmae, S., Yokoyama, S., St George-Hyslop, P., & Fraser, P. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.655076 · Cited by 128 · see citing works
Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases
Mills, J. D., & Janitz, M. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.10.030 · Cited by 114 · see citing works
<i>ABCA7</i> frameshift deletion associated with Alzheimer disease in African Americans
Cukier, H. N., Kunkle, B. W., Vardarajan, B. N., Rolati, S., Hamilton-Nelson, K. L., Kohli, M. A., Whitehead, P. L., Dombroski, B. A., Van Booven, D., Lang, R., et al. (2016) · Neurology Genetics · doi:10.1212/nxg.0000000000000079 · Cited by 100 · see citing works
Self-citationHumphries, C., Kohli, M. A., Whitehead, P. L., Mash, D. C., Pericak‐Vance, M. A., & Gilbert, J. R. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.05.003 · Cited by 47 · see citing works
Self-citationO1‐03‐02: ABCA7 Frameshift Deletion Associated with Alzheimer’s Disease in African Americans
Dykxhoorn, D. M., Cukier, H. N., Kunkle, B. W., Vardarajan, B. N., Rolati, S., Hamilton‐Nelson, K. L., Kohli, M. A., Whitehead, P. L., Booven, D. J. V., Lang, R., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.305 · Cited by 3 · see citing works
Self-citationPerry, R. T., Wiener, H. W., Harrell, L. E., & Go, R. C. P. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.05.1816 · Cited by 1 · see citing works
Flagged first, then by citations
1 of the 35 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Alzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946 · see citing works
Self-citationThe role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics
De Roeck, A., Van Broeckhoven, C., & Sleegers, K. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01994-1 · Cited by 212 · see citing works
A global view of the genetic basis of Alzheimer disease
Reitz, C., Pericak-Vance, M., Foroud, T., & Mayeux, R. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00789-z · Cited by 143 · see citing works
Self-citationAn intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer’s disease
On Behalf of the BELNEU Consortium, De Roeck, A., Duchateau, L., Van Dongen, J., Cacace, R., Bjerke, M., Van den Bossche, T., Cras, P., Vandenberghe, R., De Deyn, P. P., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1841-z · Cited by 93 · see citing works
Rajabli, F., Beecham, G., Hendrie, H., Baiyewu, O., Ogunniyi, A., Gao, S.-J., Kushch, N. A., Lipkin-Vasquez, M., Hamilton-Nelson, K., Young, J. I., et al. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1009977 · Cited by 63 · see citing works
Self-citationThe role of ATP-binding cassette subfamily A in the etiology of Alzheimer’s disease
Bossaerts, L., Cacace, R., & Broeckhoven, C. V. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00536-w · Cited by 54 · see citing works
Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy
Quan, M., Cao, S., Wang, Q., Wang, S., & Jia, J. (2023) · Phenomics · doi:10.1007/s43657-023-00098-x · Cited by 60 · see citing works
Rubin, L., Ingram, L. A., Resciniti, N. V., Ashford‐Carroll, B., Leith, K. H., Rose, A., Ureña, S., McCollum, Q., & Friedman, D. B. (2021) · Frontiers in Public Health · doi:10.3389/fpubh.2021.784958 · Cited by 25 · see citing works
ABCA7, a Genetic Risk Factor Associated with Alzheimer’s Disease Risk in African Americans
Stepler, K. E., Gillyard, T. R., Reed, C. B., Avery, T. M., Davis, J. S., & Robinson, R. A. S. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215306 · Cited by 28 · see citing works
Bossaerts, L., Hens, E., Cacace, R., Asselbergh, B., & Broeckhoven, C. V. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01346-3 · Cited by 21 · see citing works
Rare <i>ABCA7</i> variants in 2 German families with Alzheimer disease
May, P., Pichler, S., Hartl, D., Bobbili, D. R., Mayhaus, M., Spaniol, C., Kurz, A., Balling, R., Schneider, J. G., & Riemenschneider, M. (2018) · Neurology Genetics · doi:10.1212/nxg.0000000000000224 · Cited by 18 · see citing works
The Abca7V1613M variant reduces Aβ generation, plaque load, and neuronal damage
Butler, C. A., Mendoza‐Arvilla, A., Milinkeviciute, G., Cunha, C. D., Kawauchi, S., Rezaie, N., Liang, H. Y., Javonillo, D. I., Thach, A., Wang, S., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13783 · Cited by 14 · see citing works
Bossaerts, L., Hens, E., Hanseeuw, B. J., Vandenberghe, R. R., Cras, P. P., Deyn, P. P. D., Engelborghs, S., & Broeckhoven, C. V. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.04.023 · Cited by 17 · see citing works
Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans
Rajabli, F., Tosto, G., Hamilton‐Nelson, K. L., Kunkle, B. W., Vardarajan, B. N., Naj, A. C., Whitehead, P. G., Gardner, O. K., Bush, W. S., Sariya, S., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12865 · Cited by 15 · see citing works
Self-citationMoreno, J., Lanau, A. V., Madrigal, L., Pineda, A. Y. B., Hernandez, J. V., Campo, O., Soto-Ospina, A., Marín, P. A., Rishishwar, L., Norris, E. T., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0269955 · Cited by 14 · see citing works
The Early‐Onset Alzheimer's Disease Whole‐Genome Sequencing Project: Study design and methodology
Ray, N. R., Ayodele, T., Jean‐Francois, M. N., Baez, P., Fernández, M. V., Bradley, J. L., Crane, P. K., Dalgard, C. L., Kuzma, A. B., Nicaretta, H. I., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13370 · Cited by 8 · see citing works
Self-citationAlzheimer’s disease: a step closer to understanding type 3 diabetes in African Americans
Ferguson, S. A., Panos, J., Sloper, D. T., Varma, V., & Sarkar, S. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00754-z · Cited by 5 · see citing works
Yan, R. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.735170868.793558625 · Cited by 2 · see citing works
Li, J., Yue, D., Xie, W., Xiong, Z., & Wang, X. (2026) · Gene · doi:10.1016/j.gene.2026.150397
- Authors
- Kunkle, B. W., Carney, R. M., Kohli, M. A., Naj, A. C., Hamilton-Nelson, K. L., Whitehead, P. L., Wang, L., Lang, R., Cuccaro, M. L., Vance, J. M., Byrd, G. S., Beecham, G. W., Gilbert, J. R., Martin, E. R., Haines, J. L., & Pericak-Vance, M. A.
- Affiliations
- University of Miami (US)
- North Carolina Agricultural and Technical State University (US)
- Case Western Reserve University (US)
- ORCID
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 649
- Pages
- 124-129
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2604399289
- Cited by
- 19
- References
- 35
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 3 · 2019: 3 · 2018: 2
- FWCI
- 1.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1R01AG027944, UO1AG032984)
- Alzheimer’s Association (IIRG09133827)
- BrightFocus Foundation (A2011048)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- ABCA7, late-onset Alzheimer's disease, genetic risk variants, splice variants, nonsense mutation, intronic variants, 3'UTR variant, familial Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Black or African American, Female, Genotype, Humans, Introns, Male, Pedigree, Sequence Analysis, DNA, ATP-Binding Cassette Transporters, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Genetic Association Studies
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
