Copy Number Variation in Familial Parkinson Disease

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS ONE (Impact Factor: 3.23). 08/2011; 6(8):e20988. DOI: 10.1371/journal.pone.0020988
Source: PubMed


Copy number variants (CNVs) are known to cause Mendelian forms of Parkinson disease (PD), most notably in SNCA and PARK2. PARK2 has a recessive mode of inheritance; however, recent evidence demonstrates that a single CNV in PARK2 (but not a single missense mutation) may increase risk for PD. We recently performed a genome-wide association study for PD that excluded individuals known to have either a LRRK2 mutation or two PARK2 mutations. Data from the Illumina370Duo arrays were re-clustered using only white individuals with high quality intensity data, and CNV calls were made using two algorithms, PennCNV and QuantiSNP. After quality assessment, the final sample included 816 cases and 856 controls. Results varied between the two CNV calling algorithms for many regions, including the PARK2 locus (genome-wide p = 0.04 for PennCNV and p = 0.13 for QuantiSNP). However, there was consistent evidence with both algorithms for two novel genes, USP32 and DOCK5 (empirical, genome-wide p-values<0.001). PARK2 CNVs tended to be larger, and all instances that were molecularly tested were validated. In contrast, the CNVs in both novel loci were smaller and failed to replicate using real-time PCR, MLPA, and gel electrophoresis. The DOCK5 variation is more akin to a VNTR than a typical CNV and the association is likely caused by artifact due to DNA source. DNA for all the cases was derived from whole blood, while the DNA for all controls was derived from lymphoblast cell lines. The USP32 locus contains many SNPs with low minor allele frequency leading to a loss of heterozygosity that may have been spuriously interpreted by the CNV calling algorithms as support for a deletion. Thus, only the CNVs within the PARK2 locus could be molecularly validated and associated with PD susceptibility.

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    • "Copy-number variants (CNVs), usually defined as genomic deletions and duplications greater than 1 Kb, are an important cause of genetic variation in the general population [Abecasis et al., 2012; Sudmant et al., 2010] and contribute to both simple Mendelian and complex genetic traits [Girirajan et al., 2012; Pankratz et al., 2011]. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease predominantly caused by missense mutations in cardiac sarcomeric protein genes [Maron et al., 2012]. "
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    • "All de novo variants were also visually confirmed in GenomeStudio . Subjects containing numbers of CNVs 3 standard derivations from the cohort mean were removed from further analysis (Pankratz et al., 2011). To reduce the possibility of type I error, only deletions spanning 5 consecutive SNPs and duplications spanning 10 consecutive SNPs were included. "
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    • "Less is known with respect to Dock10 and Dock11, although a rare Dock10 gene deletion is associated with autism spectrum disorders (Nava et al., 2014). Although an association between Dock5 and Parkinson's disease has been suggested (Pankratz et al., 2011), the authors themselves noted that the "
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