Affiliations: [a] Department of Neurology, University at Buffalo SUNY, Buffalo, NY, USA | [b] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA | [c] Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston, TX, USA | [d] Department of Neurology, University of North Carolina, Chapel Hill, NC, USA | [e] Department of Bioinformatics, University at Buffalo, SUNY, Buffalo, NY, USA | [f] Roswell Park Cancer Institute, Buffalo, NY, USA
Correspondence:
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Correspondence to: Kinga Szigeti, University of Buffalo SUNY, 100 High Street, Buffalo, NY 14203, USA. Tel.: +1 716 859 3484; Fax: +1 716 859 7833; E-mail: szigeti@buffalo.edu.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence, which imposes a substantial public health problem. The heritability of AD is estimated at 60–80% forecasting the potential use of genetic biomarkers for risk stratification in the future. Several large scale genome-wide association studies using high frequency variants identified 10 loci accountable for only a fraction of the estimated heritability. To find the missing heritability, systematic assessment of various mutational mechanisms needs to be performed. This copy number variation (CNV) genome-wide association study with age at onset (AAO) of AD identified 5 CNV regions that may contribute to the heritability of AAO of AD. Two CNV events are intragenic causing a deletion in CPNE4. In addition, to further study the mutational load at the 10 known susceptibility loci, CNVs overlapping with these loci were also catalogued. We identified rare small events overlapping CR1 and BIN1 in AD and normal controls with opposite CNV dosage. The CR1 events are consistent with previous reports. Larger scale studies with deeper genotyping specifically addressing CNV are needed to evaluate the significance of these findings.
Keywords: Age at onset, Alzheimer's disease, copy number variation
