Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants

Abstract

This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).

SORL1 variants and risk of late-onset Alzheimer’s disease

“…Furthermore, this marker remained significant when all Caucasian sample sets, including ours, were analyzed together. Its overall effect size is a moderate 1.20, which is similar to reports from other groups in large sample sets, including ours, for markers in DAPK1 , GALP (Grupe et al, 2007), GAPD (Li et al, 2004) and LOC439999 . While markers of such effect sizes individually are likely to have limited predictive utility, their aggregation, together with APOE, may present a useful predictor of LOAD risk.…”

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…The first one used a twostage genotyping protocol and tested 17,343 SNPs in two pools of DNA from AD patients and controls from the USA and the UK, and revealed APOE to be the only gene that shows significant associations with AD [15]. This method of DNA pooling greatly reduced the cost of genotyping yet required standardization of DNA concentration in each pool to avoid bias.…”

Unraveling the biological mechanisms in Alzheimer's disease — Lessons from genomics

“…The study of Grupe et al 2007 The first published GWAS of late onset AD used a select set of more than 17,000…”

“…SNPs from 11,211 genes, chosen according to likelihood of being functional polymorphisms (Grupe et al, 2007). In the first stage of the study, genotyping was performed on a screening sample consisting of 380 AD cases and 396 control subjects from UK.…”

“…The study of Li et al 2007 A subsequent study analyzed more than 400,000 SNPs from the Affymetrix 500K platform using 753 AD cases and 736 controls of northern European ancestry from 10 Canada (Li et al, 2007). Statistically most significant signals were followed up in the 418 AD cases and 249 control subjects.…”