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PMID: 16252231 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

High-resolution whole-genome association study of Parkinson disease.

American journal of human genetics ·Vol. 77 ·No. 5 ·2005-11-00 ·Pages 685-93

Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, Pant PV, Frazer KA, Cox DR, Ballinger DG

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.

MeSH Terms
Adult Aged Aged, 80 and over Chromosome Mapping/methods Female Gene Frequency/genetics Genetic Linkage/genetics Genetic Markers/genetics Genetic Predisposition to Disease/genetics Genetic Variation Genome, Human Genotype Haplotypes Humans Linkage Disequilibrium/genetics Male Membrane Proteins/genetics Middle Aged Nerve Tissue Proteins/genetics Parkinson Disease/genetics Polymorphism, Single Nucleotide Semaphorins
Chemicals
Genetic Markers Membrane Proteins Nerve Tissue Proteins SEMA5A protein, human Semaphorins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Maraganore Demetrius M
Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA.
de Andrade Mariza
Lesnick Timothy G
Strain Kari J
Farrer Matthew J
Rocca Walter A
Pant P V Krishna
Frazer Kelly A
Cox David R
Ballinger Dennis G
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/496902
Published
2005-11-00
Epub
2005-00-09
Pages
685-93
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1271381
Subset
IM
Grants
NIEHS NIH HHS · R01 ES010751 · United States
NINDS NIH HHS · P50 NS040256 · United States
NIEHS NIH HHS · ES10751 · United States
NINDS NIH HHS · P01 NS040256 · United States
NINDS NIH HHS · NS40256 · United States
NINDS NIH HHS · R01 NS033978 · United States
NINDS NIH HHS · NS33978 · United States
NIEHS NIH HHS · ES10751-S1 · United States
Corrections
CommentIn
PMID: 16685660
CommentIn
PMID: 16685662
CommentIn
PMID: 16685663
External Links
PubMed source DOI: 10.1086/496902 PMC Full Text View journal details
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