MOLECULAR EPIDEMIOLOGY OF PARKINSON'S DISEASE

帕金森病（PD）是美国和全球不断扩大的老年人口中的常见和致残性疾病。其病因仍然不明，遗传和环境因素已被怀疑。这些研究的长期目标是阐明帕金森病的病因并确定预防方法，具体而言，我们将研究帕金森病与先前发现的与新奇寻求行为、物质使用（烟草、酒精和咖啡因）以及焦虑和抑郁障碍相关的易感基因的关系。测试的假设直接来自我们目前的工作和初步的发现。我们将采用病例未受影响的同胞对照研究设计，并将使用同胞传播不平衡检验（S-TDT）进行分析。总共将考虑9个候选易感基因，其中只有5个进行了PD的有限研究。候选易感基因包括三个解毒基因、三个多巴胺能基因和三个多巴胺能基因。我们将纳入大约10年期间从120英里半径或从5个州地区转介到马约诊所的800例PD病例。我们还将包括他们40岁或以上的符合条件的兄弟姐妹，预计将为563名受影响的先证者或兄弟姐妹和1,180名未受影响的兄弟姐妹提供血液DNA样本，这些兄弟姐妹分为521个信息性兄弟姐妹。将包括多个受影响或未受影响的兄弟姐妹。PD病例将接受临床评估和血液采样，并通过面对面访谈提供家庭信息，然后通过书面邮寄形式提供。所有40岁及以上的在世兄弟姐妹将使用经验证的电话工具进行PD筛查。筛选为PD阴性的受试者将仅通过邮寄血液采样试剂盒提供DNA。筛查阳性者将在马约诊所或家中进行临床评估，并直接采集血液DNA样本。将使用聚合酶链反应方法进行基因分型，并对受影响或未受影响状态设盲。本研究将通过使用同胞对照避免人群分层偏倚。选择用于初步分析的候选易感基因与我们发现与PD相关的人格特征、物质使用和精神疾病有关。这些基因的选择代表了一个重大的范式转变。我们还将建立一个大型的DNA库，以快速有效地测试PD的新遗传假说。本申请是根据RFA ES- 00-002（“环境在帕金森病中的作用”）提交的。我们特别强调RFA的目标，即使用分子流行病学工具评估PD的内源性（包括生物标志物）和外源性（包括饮食和生活方式）易感因素。

Parkinson's disease (PD) is a common and disabling condition in the expanding elderly population of the US and worldwide. Its etiology remains unknown and both genetic and environmental factors have been suspected. The long-term goal of the proposed studies is to clarify the etiology of PD and to identify means to prevent it. Specifically, we will study the association of PD with susceptibility genes previously found associated with novelty seeking behavior, substance use (tobacco, alcohol, and caffeine), and anxiety and depressive disorders. The hypotheses tested derive directly from our current work and preliminary findings. We will employ the case-unaffected sibling control study design and analyses will use a generalization of the sibling transmission disequilibrium test, or S-TDT. In total, nine candidate susceptibility genes will be considered, of which only five have undergone limited study for PD. The candidate susceptibility genes include three detoxification genes, three dopaminergic genes, and three serotonergic genes. We will include 800 cases of PD referred to the Mayo Clinic from a 120-mile radius or from a 5-state region during approximately a 10- year period. We will also include their eligible siblings age 40 years or above, projecting that blood DNA samples will be available for 563 affected probands or siblings and 1,180 unaffected siblings stratified in 521 informative sibships. Sibships with multiple affected or unaffected siblings will be included. PD cases will undergo a clinical assessment and blood sampling, and provide family information through a face-to-face interview followed by a written mail-in form. All living siblings ages 40 and above will be screened for PD using a validated telephone instrument. Subjects screening negative for PD will provide DNA with mail-in blood sampling kits only. Persons screening positive will be clinically assessed at the Mayo Clinic or at home, and blood DNA samples will be directly obtained. Genotyping will be performed using polymerase chain reaction methods and will be blinded to affected or unaffected status. The study will avoid population stratification bias by using sibling controls. The candidate susceptibility genes selected for primary analyses relate to personality traits, substance use, and psychiatric diseases that we have found associated with PD. The selection of these genes represents a major paradigm shift. We will also establish a large DNA bank for rapid and efficient testing of new genetic hypothesis for PD. This application is submitted in response to RFA ES- 00-002 ('The Role of the Environment in Parkinson's Disease"). We specifically address the RFA's objectives of evaluating endogenous (including biomarkers) and exogenous (including dietary and lifestyle) susceptibility factors for PD using molecular epidemiology tools.