PD GWAS Consortium

描述（由申请人提供）：帕金森病（PD）是第二常见的神经退行性疾病，影响近50万美国人。虽然已经确定了五个基因突变时可以直接导致PD，但这些基因可能导致远远低于5%的PD患者的疾病。六项全基因组关联研究（GWAS）已经完成或正在完成，以确定导致PD易感性和/或疾病发作年龄的常见变异。在已公开报道的四项研究中提名的顶级SNP或基因之间的重叠非常有限。至少有两项研究报告支持与SNCA和MAPT的关联。然而，没有凝聚力分析，像这里提出的，已经进行了这些大型GWAS研究。基于PD与一级亲属的相对风险，以及已被多个实验室证实与PD风险和发病年龄（即GBA，MAPT）相关的众多候选基因，似乎很可能还有其他尚未确定的基因也与PD易感性有关。 在本申请中，我们建议创建PD GWAS联盟，该联盟将合作使用PD遗传学研究社区的临床和生物资源来识别导致PD的基因。PD GWAS联盟不仅包括来自大多数产生PD GWAS数据的研究者，还包括提供独立复制样本的研究者。该合作小组将实现四个具体目标： 1)对来自6项独立研究的GWAS数据进行Meta和汇总分析，以确定SNP与PD易感性（5，113例病例; 5，327例对照）和发病年龄（5，113例PD病例）相关的最强证据。 2)对来自5项独立研究（4，670例病例; 4，884例对照）的GWAS数据进行汇总分析，以确定拷贝数变异，这些变异提供了与PD易感性和发病年龄相关的最强证据。 3)在5项包含吸烟数据的独立GWAS研究中进行分析，以检测可能导致PD易感性或发病年龄的基因x吸烟相互作用。 4)在先前GWAS中从未包括的2，976例PD病例和2，976例对照的复制样本中，最高优先级基因中的基因型384 SNP。 本文提出的研究将使我们能够快速推进PD遗传学，平衡该领域以进一步研究最有前途的基因组变异，并更好地了解导致疾病风险和发病年龄的机制。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting nearly 500,000 Americans. Although five genes have been identified which can directly cause PD when mutated, these genes likely contribute to disease in far fewer than 5% of all PD patients. Six Genome-Wide Association Studies (GWAS) have been or are in the process of being completed to identify common variants contributing to PD susceptibility and/or age of disease onset. There has been very limited overlap among the top SNPs or genes nominated in the four studies that have been publicly reported. At least two studies have reported support for an association with SNCA and MAPT. However, no cohesive analysis, like that proposed here, has been performed on these large GWAS studies. Based on the relative risk of PD to first degree relatives, and the numerous candidate genes that have been confirmed by multiple laboratories to have association with PD risk and age-of-onset (i.e. GBA, MAPT), it would appear highly likely that additional genes, not yet identified, must also contribute to PD susceptibility. In this application, we propose to create the PD GWAS Consortium which will collaboratively use the clinical and biological resources of the PD genetics research community to identify genes contributing to PD. The PD GWAS Consortium will consist not only of investigators from most of the groups generating PD GWAS data, but will also include investigators providing independent replication samples. This collaborative group will pursue four specific aims: 1) Perform meta and pooled analyses across the GWAS data available from six independent studies to identify the SNPs providing the strongest evidence of association with PD susceptibility (5,113 cases; 5,327 controls) and age of onset (5,113 PD cases) across studies. 2) Perform pooled analysis across the GWAS data available from five independent studies (4,670 cases; 4,884 controls) to identify copy number variants providing the strongest evidence of association with PD susceptibility and age of onset across studies. 3) Perform analyses in the five independent GWAS studies containing smoking data to test for gene x smoking interactions that may contribute to PD susceptibility or age of onset. 4) Genotype 384 SNPs in the genes of highest priority in a replication sample of 2,976 PD cases and 2,976 controls never included in a previous GWAS. The studies proposed herein will allow us to rapidly advance PD genetics, poise the field to pursue further studies of the most promising genomic variation and lead to a better understanding of the mechanisms contributing to disease risk and age of onset.