O1‐09‐04: International Genomics of Alzheimer's Disease Project (IGAP) genome‐wide association study

Abstract

Genome-wide association studies have proved successful in identifying novel susceptibility genes for Alzheimer's disease (AD). Since 2009, nine loci have been identified by work from four consortia; the European Alzheimer's Disease Initiative (EADI), the Genetic and Environmental Risk in Alzheimer's Disease (GERAD), Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE), and the Alzheimer's Disease Genetics Consortium (ADGC). These genes are ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4, and PICALM. Along with APOE, there are now 10 confirmed late-onset AD susceptibility loci. Between each round of gene discovery, an increase in sample size resulted in not only confirming the validity of earlier findings, but also identifying novel genes. To identify additional new AD loci and increase the sample size used, the International Genomics of Alzheimer's Project (IGAP) was formed by the four consortia described above. Each of the four consortia imputed genotypes using 1,000 Genomes data and study-specific results were combined in a “mega”-meta analysis. The number of cases/ controls from each consortia were as follows: EADI, 2,243/6,017; GERAD, 3,177/7,277; CHARGE, 1,337/12,888; ADGC, 10,273/10,892. The mega-meta analysis was performed using 8,537,621 SNPs. Excluding the APOE region, there were 453 SNPs with P<1.0E-8, 454 SNPs with P<1.0E-7 and P >1.0E-8, and 507 SNPs with P<1.0E-6 and P >1.0E-7. For all previously identified genes, we obtained genome-wide significant results (P<5.0E-8). From these results, SNPs with P<1.0E-3 (n = 26,268) were selected for a custom genotyping array for a replication phase using 29,348 subjects that were not part of the mega-meta analysis. Production of these arrays is in progress and genotyping will begin in winter 2012. Initial work by IGAP shows that results from previous large GWAS studies can be reproduced and are robust. From preliminary analysis of the mega-meta analysis results, we expect additional AD susceptibility loci will be identified in the replication phase.