Increased rate of sporadic and recurrent rare genic copy number variants in Parkinson's disease among Ashkenazi Jews

To date, only one genome‐wide study has assessed the contribution of copy number variants (CNVs) to Parkinson's disease (PD). We conducted a genome‐wide scan for CNVs in a case–control dataset of Ashkenazi Jewish (AJ) origin (268 PD cases and 178 controls). Using high‐confidence CNVs, we examined the global genome wide burden of large (≥100 kb) and rare (≤1% in the dataset) CNVs between cases and controls. A total of 986 such CNVs were observed in our dataset of 432 subjects. Overall global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications or number of genes affected by CNVs. Overall deletions (total CNV size and ≥2× frequency) were found 1.4 times more often in cases than in controls (P = 0.019). The large CNVs (≥500 kb) were also significantly associated with PD (P = 0.046, 1.24‐fold higher in cases than in controls). Global burden was elevated for rare CNV regions. Specifically, for OVOS2 on Chr12p11.21, CNVs were observed only in PD cases (n = 7) but not in controls (P = 0.028) and this was experimentally validated. A total of 81 PD cases carried a rare genic CNV that was absent in controls. Ingenuity pathway analysis (IPA) identified ATXN3, FBXW7, CHCHD3, HSF1, KLC1, and MBD3 in the same disease pathway with known PD genes.

[1]  Neil D. Rawlings,et al.  MEROPS: the database of proteolytic enzymes, their substrates and inhibitors , 2013, Nucleic Acids Res..

[2]  Chuong B. Do,et al.  Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database , 2012, PLoS genetics.

[3]  D. Pinto,et al.  Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics , 2012, G3: Genes | Genomes | Genetics.

[4]  Karen Marder,et al.  Genome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population , 2011, BMC Medical Genetics.

[5]  Jemma B. Wilk,et al.  Copy Number Variation in Familial Parkinson Disease , 2011, PloS one.

[6]  Marc N. Offman,et al.  A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. , 2011, American journal of human genetics.

[7]  M. Farrer,et al.  VPS35 mutations in Parkinson disease. , 2011, American journal of human genetics.

[8]  Nicholas Eriksson,et al.  Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease , 2011, PLoS genetics.

[9]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[10]  A. Minelli,et al.  New Copy Number Variations in Schizophrenia , 2010, PloS one.

[11]  S. Züchner,et al.  A Rare Novel Deletion of the Tyrosine Hydroxylase Gene in Parkinson Disease , 2010, Human mutation.

[12]  D. Cutler,et al.  Microdeletions of 3q29 confer high risk for schizophrenia. , 2010, American journal of human genetics.

[13]  Marc Cruts,et al.  Genetic Etiology of Parkinson Disease Associated with Mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 Genes: A Mutation Update , 2010, Human mutation.

[14]  Yiping Shen,et al.  Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders , 2010, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[15]  Aj Lees,et al.  Parkinson's disease (vol 373, pg 2055, 2009) , 2009 .

[16]  Christine A. Wells,et al.  A Cross-Study Transcriptional Analysis of Parkinson's Disease , 2009, PloS one.

[17]  David B. Goldstein,et al.  A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia , 2009, PLoS genetics.

[18]  W. Oyen,et al.  FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome , 2009, Neurology.

[19]  D. Hernandez,et al.  Characterization of PLA2G6 as a locus for dystonia‐parkinsonism , 2008, Annals of neurology.

[20]  M. Feldman,et al.  Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation , 2008 .

[21]  Zachary A. Szpiech,et al.  Genotype, haplotype and copy-number variation in worldwide human populations , 2008, Nature.

[22]  Joseph T. Glessner,et al.  PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. , 2007, Genome research.

[23]  K. Marder,et al.  Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease , 2007, Neurology.

[24]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[25]  K. Marder,et al.  Frequency of LRRK2 mutations in early- and late-onset Parkinson disease , 2006, Neurology.

[26]  J. Lupski,et al.  Genomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System Disorders , 2006, Neuron.

[27]  Jan Gründemann,et al.  Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase , 2006, Nature Genetics.

[28]  Houeto Jean-Luc.  [Parkinson's disease]. , 2022, La Revue du praticien.

[29]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[30]  A. Bentivoglio,et al.  PINK1 mutations are associated with sporadic early‐onset parkinsonism , 2004, Annals of neurology.

[31]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[32]  B. Oostra,et al.  DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism , 2003, Neurological Sciences.

[33]  Karen Marder,et al.  Familial aggregation of early‐ and late‐onset Parkinson's disease , 2003, Annals of neurology.

[34]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[35]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[36]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[37]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .