The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease

Abstract

Background: In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genome-wide association study (GWAS) in the Spanish population.

Methods: We genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings.

Results: Meta-analysis of our data and independent replication datasets allowed us to confirm a novel genome-wide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls).

Conclusions: Our results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases.

Figure 1

Manhattan plot of meta-analysis of five GWASs (Murcia, ADNI, GenADA, NIA, and TGEN), including a total of 3,009 cases and 3,006 controls. A total of 696,707 SNPs were common to all GWASs whereas 1,098,485 SNPs were common to at least four studies.

Figure 2

Meta-analysis and Forest plot of rs1562990, reporting odds ratio (OR) with 95% confidence interval (CI), study-specific weight, sample size and minor allele frequency (MAF) in cases and controls, for each study. The figure shows the remarkable consistency of the OR across studies.