title: 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.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Faber
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.forename: Mari
authors.initials: M
authors.lastname: Turk
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D055106:Genome-Wide Association Study; D006801:Humans; D000091042:Reelin Protein