Molecular Neurodegeneration (Jan 2012)

Both common variations and rare non-synonymous substitutions and small insertion/deletions in <it>CLU </it>are associated with increased Alzheimer risk

  • Bettens Karolien,
  • Brouwers Nathalie,
  • Engelborghs Sebastiaan,
  • Lambert Jean-Charles,
  • Rogaeva Ekaterina,
  • Vandenberghe Rik,
  • Le Bastard Nathalie,
  • Pasquier Florence,
  • Vermeulen Steven,
  • Van Dongen Jasper,
  • Mattheijssens Maria,
  • Peeters Karin,
  • Mayeux Richard,
  • St George-Hyslop Peter,
  • Amouyel Philippe,
  • De Deyn Peter P,
  • Sleegers Kristel,
  • Van Broeckhoven Christine

DOI
https://doi.org/10.1186/1750-1326-7-3
Journal volume & issue
Vol. 7, no. 1
p. 3

Abstract

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Abstract Background We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings. Results In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (ORMH = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region. Conclusions We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies.

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