High-resolution whole-genome association study of Parkinson disease

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Genetic Markers
  • Membrane Proteins
  • Nerve Tissue Proteins
  • SEMA5A protein, human