Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci.
This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM).
There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).
Five genomewide association studies (GWAS) in white populations have recently identified and confirmed 9 novel Alzheimer's disease (AD) susceptibility loci (CLU, CR1, PICALM, BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1).
Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown.
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9).
Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden.
We interpret our findings as suggesting a model wherein increased ABCA7 expression reduces AD risk and that the increased ABCA7 observed in AD reflects an inadequate compensatory change.
There were four significant associations between genotypes and phenotypes of AD patients: CR1 SNP rs11803956 correlated with Mini-Mental State Examination (MMSE) score (β=1.718, Pcorrected=0.002); ABCA7 SNP rs3752232 correlated with Rey Complex Figure Test (RCFT) copy score (β=-6.861, Pcorrected=0.013); APOE SNP rs2075650 correlated with the percentile of RCFT copy score (β=14.005, Pcorrected=0.021) and the percentile of total score in phonemic fluency (β=11.052, Pcorrected=0.035).