Analysis of copy number variation in Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals

Abstract

Copy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490-10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.

Figure 1. Forest plot of the CHRFAM7A gene.

The plot represents the meta-analysis of the CHRFAM7A gene using results from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, the National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study and the TGen study. The odds ratio (OR) and 95% confidence interval (CI) for the odds ratio for each study are represented by black squares and horizontal lines. The summary odds ratio is depicted as a black diamond.

Figure 2. Duplications overlapping the candidate genes APP and DOPEY2 in samples of the TGen cohort.

Representative UCSC Genome Browser (March 2006 (NCBI36/hg18) assembly) plots of duplications overlapping the candidate genes: (A) APP and (B) DOPEY2, in samples of the TGen cohort. The chromosomal location of the gene and probes on the Affymetrix Genomewide 6.0 array are shown. The region with the duplication for each sample relative to the gene is represented by a blue rectangle.

Figure 3. Deletions and duplications overlapping the CHRFAM7A gene in samples of the TGen cohort.

Representative UCSC Genome Browser (March 2006 (NCBI36/hg18) assembly) plots of deletions and duplications overlapping the CHRFAM7A gene in samples of the TGen cohort. The chromosomal location of the gene and probes on the Affymetrix Genomewide 6.0 array are shown. The region with the deletion for each sample relative to the gene is highlighted by a red rectangle and the region with the duplication for each sample relative to the gene is highlighted by a blue rectangle.