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Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population.
BMC Med Genet. 2011 Aug 03; 12:104.BM

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+Show Affiliations

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21812969

Citation

Liu, Xinmin, et al. "Genome-wide Association Study Identifies Candidate Genes for Parkinson's Disease in an Ashkenazi Jewish Population." BMC Medical Genetics, vol. 12, 2011, p. 104.
Liu X, Cheng R, Verbitsky M, et al. Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. BMC Med Genet. 2011;12:104.
Liu, X., Cheng, R., Verbitsky, M., Kisselev, S., Browne, A., Mejia-Sanatana, H., Louis, E. D., Cote, L. J., Andrews, H., Waters, C., Ford, B., Frucht, S., Fahn, S., Marder, K., Clark, L. N., & Lee, J. H. (2011). Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. BMC Medical Genetics, 12, 104. https://doi.org/10.1186/1471-2350-12-104
Liu X, et al. Genome-wide Association Study Identifies Candidate Genes for Parkinson's Disease in an Ashkenazi Jewish Population. BMC Med Genet. 2011 Aug 3;12:104. PubMed PMID: 21812969.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. AU - Liu,Xinmin, AU - Cheng,Rong, AU - Verbitsky,Miguel, AU - Kisselev,Sergey, AU - Browne,Andrew, AU - Mejia-Sanatana,Helen, AU - Louis,Elan D, AU - Cote,Lucien J, AU - Andrews,Howard, AU - Waters,Cheryl, AU - Ford,Blair, AU - Frucht,Steven, AU - Fahn,Stanley, AU - Marder,Karen, AU - Clark,Lorraine N, AU - Lee,Joseph H, Y1 - 2011/08/03/ PY - 2011/01/27/received PY - 2011/08/03/accepted PY - 2011/8/5/entrez PY - 2011/8/5/pubmed PY - 2011/10/27/medline SP - 104 EP - 104 JF - BMC medical genetics JO - BMC Med Genet VL - 12 N2 - 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. SN - 1471-2350 UR - https://www.unboundmedicine.com/medline/citation/21812969/Genome_wide_association_study_identifies_candidate_genes_for_Parkinson's_disease_in_an_Ashkenazi_Jewish_population_ L2 - https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-12-104 DB - PRIME DP - Unbound Medicine ER -