Lancet. 2011 Feb 19;377(9766):641-9. doi: 10.1016/S0140-6736(10)62345-8. Epub 2011 Feb 1.
Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease.
We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated.
The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7-69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23-2·83) compared with 1·00 in the lowest quintile of disease risk.
These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies.
Wellcome Trust, National Institute on Aging, and US Department of Defense.
全基因组关联研究（GWAS）已经将两个基因座（MAPT 和 SNCA）与帕金森病的风险联系起来。我们旨在确定帕金森病的新风险基因座。
我们对来自美国和欧洲的五项帕金森病 GWAS 的数据集进行了荟萃分析，以确定与帕金森病相关的基因座（发现阶段）。然后，我们在独立的样本系列中对显著相关的基因座进行了复制分析。从发现和复制阶段的综合估计中计算了人群归因风险的估计值，并计算了在发现阶段确定的基因座的风险特征估计值。
发现阶段包括 5333 例病例和 12019 例对照样本，基因分型和 imputed 数据为 7689524 SNPs。复制阶段包括 7053 例病例和 9007 例对照样本。我们确定了 11 个超过全基因组显著性阈值（p<5×10(-8))的基因座。其中 6 个是先前确定的基因座（MAPT、SNCA、HLA-DRB5、BST1、GAK 和 LRRK2），5 个是新确定的基因座（ACMSD、STK39、MCCC1/LAMP3、SYT11 和 CCDC62/HIP1R）。综合人群归因风险为 60.3%（95%CI 43.7-69.3）。在风险特征分析中，疾病风险最高五分位数的优势比为 2.51（95%CI 2.23-2.83），而疾病风险最低五分位数的优势比为 1.00。
这些数据提供了对帕金森病遗传学和疾病分子病因的深入了解，为未来的治疗提供了潜在靶点。
威康信托基金会、美国国家老龄化研究所和美国国防部。
