MOLECULAR EPIDEMIOLOGY OF PARKINSON'S DISEASE

帕金森氏病(PD)是美国和世界范围内不断增长的老年人口中的一种常见和致残的疾病。其病因尚不清楚，遗传和环境因素都已被怀疑。拟议研究的长期目标是阐明帕金森病的病因并找出预防方法。具体地说，我们将研究PD与先前发现的与寻求新奇行为、物质使用(烟草、酒精和咖啡因)以及焦虑和抑郁障碍有关的易感基因的关联。测试的假设直接来自我们目前的工作和初步发现。我们将采用病例未受影响的同胞对照研究设计，分析将使用推广的同胞传递不平衡检验，或S-TDT。总共将考虑9个候选易感基因，其中只有5个进行了有限的帕金森病研究。候选易感基因包括3个解毒基因、3个多巴胺能基因和3个5-羟色胺能基因。我们将包括在大约10年的时间里，从半径120英里或5个州的地区转诊到梅奥诊所的800例帕金森病患者。我们还将包括他们40岁或以上的符合条件的兄弟姐妹，预计将提供563个受影响的先证者或兄弟姐妹的血液DNA样本，以及521个信息丰富的兄弟姐妹中的1180个未受影响的兄弟姐妹的血液DNA样本。有多个受影响或未受影响兄弟姐妹的兄弟姐妹将被包括在内。帕金森病患者将接受临床评估和血液采样，并通过面对面访谈和书面邮寄表格提供家庭信息。所有40岁及以上的在世兄弟姐妹将使用经过验证的电话仪器进行帕金森病筛查。帕金森病筛查阴性的受试者将只提供DNA邮寄血样试剂盒。筛查呈阳性的人将在梅奥诊所或家中接受临床评估，并将直接获取血液DNA样本。基因分型将使用聚合酶链式反应方法进行，并将被盲化为受影响或未受影响的状态。这项研究将通过使用兄弟姐妹对照来避免人口分层偏见。初步分析选择的候选易感基因与我们发现的与帕金森病相关的人格特征、药物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DNA文库，以快速有效地测试帕金森病的新遗传假说。本申请是根据RFA ES-00-002(《环境在帕金森病中的作用》)提交的。我们特别针对RFA使用分子流行病学工具评估内源性(包括生物标志物)和外源性(包括饮食和生活方式)帕金森病易感因素的目标。

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.