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

  • De Roeck, Arne1, 2
  • Duchateau, Lena1, 2
  • Van Dongen, Jasper1, 2
  • Cacace, Rita1, 2
  • Bjerke, Maria3
  • Van den Bossche, Tobi1, 2, 4, 5
  • Cras, Patrick4, 5
  • Vandenberghe, Rik6, 7
  • De Deyn, Peter P.2, 5
  • Engelborghs, Sebastiaan3, 5
  • Van Broeckhoven, Christine1, 2
  • Sleegers, Kristel1, 2
  • 1 University of Antwerp-CDE, Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Universiteitsplein 1, Antwerp, 2610, Belgium , Antwerp (Belgium)
  • 2 University of Antwerp, Institute Born-Bunge, Antwerp, Belgium , Antwerp (Belgium)
  • 3 University of Antwerp (UAntwerp), Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Antwerp, Belgium , Antwerp (Belgium)
  • 4 Antwerp University Hospital, Department of Neurology, Edegem, Belgium , Edegem (Belgium)
  • 5 Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium , Antwerp (Belgium)
  • 6 KU Leuven, Department of Neurosciences, Faculty of Medicine, Leuven, Belgium , Leuven (Belgium)
  • 7 University Hospitals Leuven, Department of Neurology, Leuven, Belgium , Leuven (Belgium)
Published Article
Acta Neuropathologica
Publication Date
Mar 27, 2018
DOI: 10.1007/s00401-018-1841-z
Springer Nature


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 β1–42 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.

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