title: Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk.
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 (OR(MH) = 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.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerpen, Belgium. kristel.sleegers@molgen.vib-ua.be.
authors.forename: Karolien
authors.initials: K
authors.lastname: Bettens
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Nathalie
authors.initials: N
authors.lastname: Le Bastard
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.forename: Steven
authors.initials: S
authors.lastname: Vermeulen
authors.forename: Jasper
authors.initials: J
authors.lastname: Van Dongen
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D002170:Canada; D002874:Chromosome Mapping; D051152:Clusterin / Q000235:genetics*; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017384:Sequence Deletion; D044465:White People / Q000235:genetics
chemical_list: D051152:Clusterin