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&#x3C;.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&#x3C;.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=7.62E-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=1.70E-5). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P&#x3C;.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=9.07E-6; P=2.96E-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.
 Note: The following instruments were used: 1)clinical assessments form and manual; 2) sibling screening form and manual; 3) unrelated
 control screening and manual; and 4) risk factors questionnaire and manual. All cases underwent #1, as did sibling controls screening
 positive (see below). Unrelated controls were not examined. All siblings underwent #2. All unrelated controls underwent #3. All subjects
 (cases, sibling controls, and unrelated controls) underwent #4.
 
 Any publications using the data are to cite the original American Journal of Human Genetics article (Maraganore et al., 2005).
 Investigators using the data collection instruments are to acknowledge Drs. Maraganore and Rocca, and cite grants ES-10751 and NS-33978.

Mayo-Perlegen LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) Collaboration

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