Abstract
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 (r2 = 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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease clinically characterized by memory impairment and pathologically characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain
All genotyping data were subjected to a strict quality control process including call rates, Hardy-Weinberg equilibrium (HWE) test, sample heterogeneity, gender check and population stratification
Since limited number of markers are shared between Affymetrix 550 K (GenADA) and Illumina HumanHap 550/610 platforms (Pfizer and Alzheimer’s Disease NeuroImaging Initiative (ADNI)), we imputed the Genotype-Phenotype Alzheimer’s disease Associations (GenADA) data set to the nonsingleton HapMap SNPs based on the HapMap III reference haplotypes in unrelated Caucasian individuals
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease clinically characterized by memory impairment and pathologically characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain. Less than 5% of AD patients can be categorized as early-onset disease (diagnosis before age 65). The cause for this subset of disease has been linked to gene mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) (reviewed in [1]) and duplications of APP [2]. The major form of AD, late-onset AD (LOAD), has a strong genetic component. APOE is the primary genetic risk factor in LOAD [4]
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