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An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer's disease

(2018) ACTA NEUROPATHOLOGICA. 135(6). p.827-837
Author
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Abstract
Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer's disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3-24.2)], and VNTR length inversely correlated with amyloid beta(1-42) in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular-which is formed through exon 19 skipping-lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.
Keywords
Alzheimer's disease, ATP-Binding Cassette, Sub-Family A, Member 7 (ABCA7), Variable number tandem repeat (VNTR), Alternative splicing, Cerebrospinal fluid (CSF) biomarkers, GENOME-WIDE ASSOCIATION, OF-FUNCTION VARIANTS, GENE-EXPRESSION, IDENTIFIES VARIANTS, NATIONAL INSTITUTE, COMMON VARIANTS, RARE VARIANTS, AMYLOID-BETA, BRAIN, LOCI

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MLA
De Roeck, Arne et al. “An Intronic VNTR Affects Splicing of ABCA7 and Increases Risk of Alzheimer’s Disease.” ACTA NEUROPATHOLOGICA 135.6 (2018): 827–837. Print.
APA
De Roeck, Arne, Duchateau, L., Van Dongen, J., Cacace, R., Bjerke, M., Van den Bossche, T., Cras, P., et al. (2018). An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer’s disease. ACTA NEUROPATHOLOGICA, 135(6), 827–837.
Chicago author-date
De Roeck, Arne, Lena Duchateau, Jasper Van Dongen, Rita Cacace, Maria Bjerke, Tobi Van den Bossche, Patrick Cras, et al. 2018. “An Intronic VNTR Affects Splicing of ABCA7 and Increases Risk of Alzheimer’s Disease.” Acta Neuropathologica 135 (6): 827–837.
Chicago author-date (all authors)
De Roeck, Arne, Lena Duchateau, Jasper Van Dongen, Rita Cacace, Maria Bjerke, Tobi Van den Bossche, Patrick Cras, Rik Vandenberghe, Peter P De Deyn, Sebastiaan Engelborghs, Christine Van Broeckhoven, Kristel Sleegers, on behalf of the BELNEU Consortium, Anne Sieben, Jan De Bleecker, and Patrick Santens. 2018. “An Intronic VNTR Affects Splicing of ABCA7 and Increases Risk of Alzheimer’s Disease.” Acta Neuropathologica 135 (6): 827–837.
Vancouver
1.
De Roeck A, Duchateau L, Van Dongen J, Cacace R, Bjerke M, Van den Bossche T, et al. An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer’s disease. ACTA NEUROPATHOLOGICA. 2018;135(6):827–37.
IEEE
[1]
A. De Roeck et al., “An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer’s disease,” ACTA NEUROPATHOLOGICA, vol. 135, no. 6, pp. 827–837, 2018.
@article{8618374,
  abstract     = {Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer's disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3-24.2)], and VNTR length inversely correlated with amyloid beta(1-42) in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular-which is formed through exon 19 skipping-lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.},
  author       = {De Roeck, Arne and Duchateau, Lena and Van Dongen, Jasper and Cacace, Rita and Bjerke, Maria and Van den Bossche, Tobi and Cras, Patrick and Vandenberghe, Rik and De Deyn, Peter P and Engelborghs, Sebastiaan and Van Broeckhoven, Christine and Sleegers, Kristel and BELNEU Consortium, on behalf of the and De Bleecker, Jan and Santens, Patrick},
  issn         = {0001-6322},
  journal      = {ACTA NEUROPATHOLOGICA},
  keywords     = {Alzheimer's disease,ATP-Binding Cassette,Sub-Family A,Member 7 (ABCA7),Variable number tandem repeat (VNTR),Alternative splicing,Cerebrospinal fluid (CSF) biomarkers,GENOME-WIDE ASSOCIATION,OF-FUNCTION VARIANTS,GENE-EXPRESSION,IDENTIFIES VARIANTS,NATIONAL INSTITUTE,COMMON VARIANTS,RARE VARIANTS,AMYLOID-BETA,BRAIN,LOCI},
  language     = {eng},
  number       = {6},
  pages        = {827--837},
  title        = {An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer's disease},
  url          = {http://dx.doi.org/10.1007/s00401-018-1841-z},
  volume       = {135},
  year         = {2018},
}

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