title: Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population.
abstract: BACKGROUND
  To date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified.
  
  
  METHODS
  We applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls.
  
  
  RESULTS
  We identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 × 10(-5)). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10(-4)), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10(-4)) and GBA (Chr1q21; rs2990245, p = 0.015).
  
  
  CONCLUSIONS
  We have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Miguel
authors.initials: M
authors.lastname: Verbitsky
authors.forename: Sergey
authors.initials: S
authors.lastname: Kisselev
authors.forename: Andrew
authors.initials: A
authors.lastname: Browne
authors.forename: Helen
authors.initials: H
authors.lastname: Mejia-Sanatana
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
authors.forename: Lucien J
authors.initials: LJ
authors.lastname: Cote
authors.forename: Howard
authors.initials: H
authors.lastname: Andrews
authors.forename: Cheryl
authors.initials: C
authors.lastname: Waters
authors.forename: Blair
authors.initials: B
authors.lastname: Ford
authors.forename: Steven
authors.initials: S
authors.lastname: Frucht
authors.forename: Stanley
authors.initials: S
authors.lastname: Fahn
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D030541:Databases, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors