High-resolution whole-genome association study of Parkinson disease

Demetrius M. Maraganore, Mariza De Andrade, Timothy C. Lesnick, Kari J. Strain, Matthew J. Farrer, Walter A. Rocca, P. V.Krishna Pant, Kelly A. Frazer, David R. Cox, Dennis C. Ballinger

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364 Scopus citations

Abstract

We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P < .01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P < .01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P = 7.62 × 10 -6). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P = 1.70 × 10-5). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P < .05 ) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n = 941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P = 9.07 × 10-6; P = 2.96 × 10-5) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNTPs in conferring PD susceptibility.

Original languageEnglish (US)
Pages (from-to)685-693
Number of pages9
JournalAmerican journal of human genetics
Volume77
Issue number5
DOIs
StatePublished - Nov 2005

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Maraganore, D. M., De Andrade, M., Lesnick, T. C., Strain, K. J., Farrer, M. J., Rocca, W. A., Pant, P. V. K., Frazer, K. A., Cox, D. R., & Ballinger, D. C. (2005). High-resolution whole-genome association study of Parkinson disease. American journal of human genetics, 77(5), 685-693. https://doi.org/10.1086/496902