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.
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