Genome-wide Copy Number Variation Analysis in Alzheimer´s Disease Family Samples

Objectives: Over 200 rare and fully penetrant pathogenic mutations in APP, PSEN1 and PSEN2 cause a subset of early-onset familial Alzheimer's disease (AD), while APOE-e4 is the only established risk factor in late-onset forms of AD. Recent studies suggest structural variations in the genome, including copy number variations (CNVs), account for more than 10 fold higher genotypic variation in humans compared to nucleotide sequence variants. In this study, we set out identify pathogenic CNVs in three large collections of AD family cohorts, comprising 2634 well-characterized pedigrees. Methods: Using high-density DNA microarray data we performed a comprehensive genome-wide CNV analysis in close to 6400 samples from our collection of AD families. CNV segmentation was performed using PennCNV and Golden Helix SVS software tools. CNVs were analyzed using a multi-pronged approach, including a custom software-script to identify CNVs segregating with affected siblings in the test families. Pedigree Based Association Testing (PBAT) was performed using probe intensities, and markers for CNVs, as well as, copy number polymorphisms (CNPs). Results: In addition to confirming two previously reported families carrying APP duplication, our analysis revealed ten novel private CNVs in ten EOFAD families. Furthermore, PBAT confirmed one previously associated genomic loci at Chr. 14q11.2, and also revealed two novel regions showing association with affection status. Conclusions: We have identified several novel CNVs that overlap genes associated with critical neuronal pathways and implicated in neurodegenerative diseases. To our knowledge, this is the first study reporting rare gene-rich CNVs in AD likely to have pathogenic consequences in AD.