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

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.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.Genome-wide association (GWA) studies lead to long-awaited breakthroughs in the genetics of late-onset Alzheimer disease (AD) [MIM 104300] [1] by providing conclusive genetic association evidence for novel AD risk genes [2-5]. Notably, GWA significance with similar effect sizes was reached for the top single nucleotide polymorphism (SNP) rs11136000 in the clusterin gene (CLU) [MIM 185430] [1]. The CLU protein (also known as apolipoprotein J) is a multifunctional protein showing functional similarities with the major apolipoprotein of the brain, apolipoprotein E (APOE) [6]. In relation to AD, CLU expression