TY - JOUR
T1 - High-resolution whole-genome association study of Parkinson disease
AU - Maraganore, Demetrius M.
AU - De Andrade, Mariza
AU - Lesnick, Timothy C.
AU - Strain, Kari J.
AU - Farrer, Matthew J.
AU - Rocca, Walter A.
AU - Pant, P. V.Krishna
AU - Frazer, Kelly A.
AU - Cox, David R.
AU - Ballinger, Dennis C.
N1 - Funding Information:
This study was supported primarily by a Michael J. Fox Foundation Linked Efforts to Accelerate Parkinson's Solutions award. We also received support from National Institutes of Health grants ES10751, ES10751-S1, NS33978, and NS40256. We acknowledge the outstanding contributions of the many Perlegen Sciences and Mayo employees who provided technical and infrastructural support for this work. But mostly, we thank the patients and study subjects who made this work possible and who give it value.
PY - 2005/11
Y1 - 2005/11
N2 - 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.
AB - 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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U2 - 10.1086/496902
DO - 10.1086/496902
M3 - Article
C2 - 16252231
AN - SCOPUS:27244451809
SN - 0002-9297
VL - 77
SP - 685
EP - 693
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -