High-resolution whole-genome association study of Parkinson disease - PubMed (original) (raw)
High-resolution whole-genome association study of Parkinson disease
Demetrius M Maraganore et al. Am J Hum Genet. 2005 Nov.
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 x 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 x 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 x 10(-6); P=2.96 x 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 SNPs in conferring PD susceptibility.
Comment in
- Conflicting results regarding the semaphorin gene (SEMA5A) and the risk for Parkinson disease.
Clarimon J, Scholz S, Fung HC, Hardy J, Eerola J, Hellstrom O, Chen CM, Wu YR, Tienari PJ, Singleton A. Clarimon J, et al. Am J Hum Genet. 2006 Jun;78(6):1082-4; author reply 1092-4. doi: 10.1086/504727. Am J Hum Genet. 2006. PMID: 16685660 Free PMC article. No abstract available. - No evidence for association with Parkinson disease for 13 single-nucleotide polymorphisms identified by whole-genome association screening.
Goris A, Williams-Gray CH, Foltynie T, Compston DA, Barker RA, Sawcer SJ. Goris A, et al. Am J Hum Genet. 2006 Jun;78(6):1088-90; author reply 1092-4. doi: 10.1086/504726. Am J Hum Genet. 2006. PMID: 16685662 Free PMC article. No abstract available. - A case-control association study of the 12 single-nucleotide polymorphisms implicated in Parkinson disease by a recent genome scan.
Li Y, Rowland C, Schrodi S, Laird W, Tacey K, Ross D, Leong D, Catanese J, Sninsky J, Grupe A. Li Y, et al. Am J Hum Genet. 2006 Jun;78(6):1090-2; author reply 1092-4. doi: 10.1086/504725. Am J Hum Genet. 2006. PMID: 16685663 Free PMC article. No abstract available.
References
Web Resources
- Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for PD, SNCA, parkin, UCHL1, MAPT, DJ1, PINK1, PARK3, PARK8, PARK9, PARK10, PARK11, LRRK2, SEMA5A, GALNT3, and PRDM2)
- SeattleSNPs, http://pga.gs.washington.edu/ (for PGA)
References
- Barzilai A, Zilkha-Falb R, Daily D, Stern N, Offen D, Ziv I, Melemed E, Shirvan A (2000) The molecular mechanism of dopamine-induced apoptosis: identification and characterization of genes that mediate dopamine toxicity. J Neural Transm Suppl 60:59–76 - PubMed
- Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MCJ, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–25910.1126/science.1077209 - DOI - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R01 ES010751/ES/NIEHS NIH HHS/United States
- P50 NS040256/NS/NINDS NIH HHS/United States
- ES10751/ES/NIEHS NIH HHS/United States
- P01 NS040256/NS/NINDS NIH HHS/United States
- NS40256/NS/NINDS NIH HHS/United States
- R01 NS033978/NS/NINDS NIH HHS/United States
- NS33978/NS/NINDS NIH HHS/United States
- ES10751-S1/ES/NIEHS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases