Copy number variation in familial parkinson disease

Nathan Pankratz, Alexandra Dumitriu, Kurt N. Hetrick, Mei Sun, Jeanne C. Latourelle, Jemma B. Wilk, Cheryl Halter, Kimberly F. Doheny, James F. Gusella, William C. Nichols, Richard H. Myers, Tatiana Foroud, Anita L. DeStefano

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere20988
JournalPLoS One
Volume6
Issue number8
DOIs
StatePublished - 2011

Fingerprint

Parkinson disease
Parkinson Disease
Genes
loci
DNA
Association reactions
Genome
mutation
Mutation
missense mutation
genome
minisatellite repeats
Loss of Heterozygosity
Genome-Wide Association Study
Disease Susceptibility
Missense Mutation
Electrophoresis
Gene Frequency
Artifacts
gel electrophoresis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pankratz, N., Dumitriu, A., Hetrick, K. N., Sun, M., Latourelle, J. C., Wilk, J. B., ... DeStefano, A. L. (2011). Copy number variation in familial parkinson disease. PLoS One, 6(8), [e20988]. https://doi.org/10.1371/journal.pone.0020988

Copy number variation in familial parkinson disease. / Pankratz, Nathan; Dumitriu, Alexandra; Hetrick, Kurt N.; Sun, Mei; Latourelle, Jeanne C.; Wilk, Jemma B.; Halter, Cheryl; Doheny, Kimberly F.; Gusella, James F.; Nichols, William C.; Myers, Richard H.; Foroud, Tatiana; DeStefano, Anita L.

In: PLoS One, Vol. 6, No. 8, e20988, 2011.

Research output: Contribution to journalArticle

Pankratz, N, Dumitriu, A, Hetrick, KN, Sun, M, Latourelle, JC, Wilk, JB, Halter, C, Doheny, KF, Gusella, JF, Nichols, WC, Myers, RH, Foroud, T & DeStefano, AL 2011, 'Copy number variation in familial parkinson disease', PLoS One, vol. 6, no. 8, e20988. https://doi.org/10.1371/journal.pone.0020988
Pankratz N, Dumitriu A, Hetrick KN, Sun M, Latourelle JC, Wilk JB et al. Copy number variation in familial parkinson disease. PLoS One. 2011;6(8). e20988. https://doi.org/10.1371/journal.pone.0020988
Pankratz, Nathan ; Dumitriu, Alexandra ; Hetrick, Kurt N. ; Sun, Mei ; Latourelle, Jeanne C. ; Wilk, Jemma B. ; Halter, Cheryl ; Doheny, Kimberly F. ; Gusella, James F. ; Nichols, William C. ; Myers, Richard H. ; Foroud, Tatiana ; DeStefano, Anita L. / Copy number variation in familial parkinson disease. In: PLoS One. 2011 ; Vol. 6, No. 8.
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