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. 2005 Nov;77(5):685-93.
doi: 10.1086/496902. Epub 2005 Sep 9.

High-resolution whole-genome association study of Parkinson disease

Demetrius M Maraganore  1 , Mariza de Andrade, Timothy G Lesnick, Kari J Strain, Matthew J Farrer, Walter A Rocca, P V Krishna Pant, Kelly A Frazer, David R Cox, Dennis G Ballinger
Affiliations

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.

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References

Web Resources

    1. Entrez Gene, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
    1. GeneCards, http://bioinfo.weizmann.ac.il/cards/index.shtml
    1. 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)
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