Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Abstract

Recently genome-wide association studies have identified significant association between Alzheimer's disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (.100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a 470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs. Alzheimer's disease (AD) is the most common form of dementia, affecting 30% of individuals over 80 years of age (Mayeux 2003). The hallmark of AD brain pathology is characterized by the accumulation of a neurotoxic proteolytic derivative of the amyloid precursor protein (APP; Ab peptides) and the formation of intraneuronal tau-associated neurofibrillary tangles. The majority of AD cases are sporadic (95%), with onset after 65 years of age. One half of the genetic variance is attributable to mutations in APP, PSEN1, PSEN2, and the APOE e4-allele, and they have been shown to cause the overproduction or reduced clearance of Ab (Rogaeva et al. 2006). More recently, it was demonstrated that single nucleotide polymorphisms (SNP) in SORL1 are significantly associated with late-onset AD in several independent cohorts (Rogaeva et al. 2007;Reitz et al. 2011). In addition,

Mutation analysis of patients with neurodegenerative disorders using NeuroX array

“…However, the role of copy number variations (CNVs) and recessive inheritance (e.g. estimated based on runs of homozygosity) need further exploration (Ghani, et al, 2012, Ghani, et al, 2013a). …”

Alzheimer's Disease

“…CHRNA7 was found to be one of the genes with suggestive significance (Heinzen et al, 2010). A similar study on Caribbean Hispanics revealed nominal association at Chr15q11.2 (Ghani et al, 2012) encompassing five genes. In a study on the AD neuroimaging initiative samples, significant higher burden of CNV-region deletions was found in mild cognitive impairment (MCI) and AD cases compared to controls (Guffanti et al, 2013).…”

Novel Susceptibility Loci for Alzheimer's DXSisease

“…Due to the complexity of sequence alterations caused the mechanistic links between structural variants and phenotypes of interest are often difficult to assess and prove. Apart from the CNVs described in CR1 [71] and a ∼470 kb duplication on chromosome 15q11.2 encompassing five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1 and WHAMML1) [122], no structural variants have been reported in AD. However, this is a rapidly developing field and continues to be an area of study.…”