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

Abstract

BackgroundWe 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.ResultsIn 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.ConclusionsWe 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.

Association of CLU and TLR2 gene polymorphisms with late-onsetAlzheimer disease in a northwestern Iranian population

“…Furthermore, APOE and CLU have been shown to cooperate in suppressing Aβ deposition and APOE and CLU may critically modify Aβ clearance at the blood-brain barrier, suggesting a role for clusterin in the amyloidogenic pathway. CLU levels are increased in proportion to APOE-ε4 allele dose, suggesting an induction of clusterin in individuals with low APOE levels (12).…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…Harold et al in their GWAS paper had reported the variant as being in strong LD with rs11136000 (r 2 0.976, D' 0.998), which showed a similar level of association with AD as rs11136000 in their data (Harold et al 2009). In other studies, the SNP has not been found to be significantly associated with AD, perhaps due to insufficient sample sizes to give the power required (Guerreiro et al 2010;Bettens et al 2012). In the imputed data, rs7982 showed a more significant association with AD than did rs11136000.…”

“…Several published studies have sought to characterise the source of the association signal within CLU, generally focussing on exonic regions, and consistently, no coding variants which can explain the GWAS signal have been found (Guerreiro et al 2010;Bettens et al 2012;Ferrari et al 2012). Given the assumption that the GWAS SNP is tagging a variant or variants implicated in AD risk at the CLU locus, it is logical to turn the search to non-coding variants.…”

“…Although attempts to track down the underlying causative variants have been more extensive for CLU (Harold et al 2009;Guerreiro et al 2010;Bettens et al 2012;Ferrari et al 2012) than for PICALM (Harold et al 2009;Ferrari et al 2012;Schnetz-Boutaud et al 2012), neither have been particularly fruitful, with no real explanatory causal variation found.…”

Investigating Splicing Variants Uncovered by Next-Generation Sequencing the Alzheimer’s Disease Candidate Genes, CLU, PICALM, CR1, ABCA7, BIN1, the MS4A Locus, CD2AP, EPHA1 and CD33

“…Examples include CLU [4], CLU, PICALM and CR1 [5], ABCA7 [6] and ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4/MS4A6A [7]. All studies, apart from [5], have used targeted exome sequencing, ignoring variants which may be found in the noncoding and intronic regions of the loci.…”