New gene variants associated with Alzheimer's disease risk

10 September 2009

Alzheimer’s disease is the most common form of dementia, affecting around 417,000 people in the UK (according to the Alzheimer’s Society website). The common, late-onset form of the disease, which accounts for 90% of all cases, shows a relatively high degree of heritability, but genetic contributions to disease risk are undoubtedly complex. Despite large amounts of research conducted to date, the APOE gene is still the only one to be established unequivocally as a susceptibility gene. Harold et al. recently reported the findings of their two-stage genome-wide association (GWA) study started almost two years ago (see previous news). Association between Alzheimer’s disease risk and genetic variants in two genes (CLU and PICALM) was identified, and the well established APOE association replicated [Harold et al. (2009) Nat Genet 6 September doi:10.1038/ng.440].

The first stage of the study made use of almost 4,000 Alzheimer’s disease patients and 8,000 healthy controls of American, British and European ancestry, with genotyping data for 530,000 SNPs. Thirteen SNPs at the APOE locus were found to be statistically significant at a genome-wide threshold of P ≤ 9.4 x 10-8. Two other SNPs reached this significance level representing newly identified associations. The first SNP (rs11136000) is located within an intron of the CLU gene (which encodes a major brain apolipoprotein, clusterin) on chromosome 8. The second SNP (rs3851179) is located 88.5kb from the PICALM gene (which encodes the phosphatidylinositol-binding clathrin assembly protein) on chromosome 11. In the second stage of this study, these two SNPs were genotyped in an independent sample of 2,000 Alzheimer’s disease patients and 2,300 age-matched and cognitively screened controls of European ancestry, and shown to be independently associated in this sample. A meta-analysis combining data from both stages also showed significant association for both SNPs (rs11136000 P = 8.5 x 10-10, OR = 0.861, 95% CI 0.82-0.90; rs3851179 P = 1.3 x 10-9, OR = 0.859, 95% CI 0.82-0.90).

The investigators then moved their focus to trying to identify functional variants responsible for these associations. A synonymous SNP (rs7982) located in exon 5 of the CLU gene was identified as being in strong linkage disequilibrium with rs11136000 and also showed similar levels of evidence for association with the combined stage1 and stage 2 study data. This SNP is located in a region coding for the beta chain of the clusterin protein and may influence a predicted exon splicing enhancer. Several potentially functional SNPs were identified at the PICALM locus, and two of these show evidence of association with putative transcription factor binding and exon splicing functions; all these functions could influence gene expression.

Comment: Well-conducted and showing robust evidence for association, the study by Harold et al. identifies new genetic variants in two gene loci of interest, providing further avenues of investigation in uncovering the genetic architecture of Alzheimer’s disease. The study by Lambert et al. [Lambert et al. (2009) Nat Genet 6 September doi:10.1038/ng439], also published in the same issue of Nature Genetics, also provides replicated evidence for the CLU gene in 5,000 Alzheimer’s disease patients and 8,000 controls of European ancestry. These two studies provide interesting epidemiological evidence for Alzheimer’s disease genetics, although much more work is required before any possible clinical benefits could be realised.

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