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Recent GWAS studies focused on uncovering novel genetic loci related to AD have revealed associations with variants near  CLU ,  CR1 ,  PICALM  and  BIN1 . In this study, we conducted a genome-wide association study in an independent set of 1034 cases and 1186 controls using the Illumina genotyping platforms. By coupling our data with available GWAS datasets from the ADNI and GenADA, we replicated the original associations in both  PICALM  (rs3851179) and  CR1  (rs3818361). The  PICALM  variant seems to be non-significant after we adjusted for  APOE e4  status. We further tested our top markers in 751 independent cases and 751 matched controls. Besides the markers close to the APOE locus, a marker (rs12989701) upstream of  BIN1  locus was replicated and the combined analysis reached genome-wide significance level (p = 5E-08). We combined our data with the published Harold et al. study and meta-analysis with all available 6521 cases and 10360 controls at the  BIN1  locus revealed two significant variants (rs12989701, p = 1.32E-10 and rs744373, p = 3.16E-10) in limited linkage disequilibrium (r 2  = 0.05) with each other. The independent contribution of both SNPs was supported by haplotype conditional analysis. We also conducted multivariate analysis in canonical pathways and identified a consistent signal in the downstream pathways targeted by Gleevec (P = 0.004 in Pfizer; P = 0.028 in ADNI and P = 0.04 in GenADA). We further tested variants in  CLU ,  PICALM ,  BIN1  and  CR1  for association with disease progression in 597 AD patients where longitudinal cognitive measures are sufficient. Both the  PICALM  and  CLU  variants showed nominal significant association with cognitive decline as measured by change in Clinical Dementia Rating-sum of boxes (CDR-SB) score from the baseline but did not pass multiple-test correction. Future experiments will help us better understand potential roles of these genetic loci in AD pathology.

Meta-Analysis for Genome-Wide Association Study Identifies Multiple Variants at the BIN1 Locus Associated with Late-Onset Alzheimer's Disease