Genome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population

BMC Medical Genetics

Research Article

Cheryl Waters¹  Blair Ford¹  Andrew Browne²  Sergey Kisselev²  Rong Cheng³  Helen Mejia-Sanatana³  Lucien J Cote³  Howard Andrews⁴  Xinmin Liu⁵  Miguel Verbitsky⁵  Stanley Fahn⁵  Steven Frucht⁵  Lorraine N Clark⁶  Joseph H Lee⁷  Elan D Louis⁸  Karen Marder⁹ 

[1] Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA;New York State Psychiatric Institute, Data Coordinating Center, New York, NY, USA;Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Center for Human Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA;Center for Human Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA;Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Psychiatry, Columbia University Medical Center, NYC, NY, USA;

关键词: Parkinson's disease;    GWAS;    Ashkenazi Jews;    case-control study;    candidate genes;   

DOI  :  10.1186/1471-2350-12-104

 received in 2011-01-27, accepted in 2011-08-03,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundTo 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.MethodsWe 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.ResultsWe 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).ConclusionsWe 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.

【 授权许可】

Unknown   
© Liu et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.