GENETIC EPIDEMIOLOGY OF PD--MITOCHONDRIAL INHERITANCE

PD遗传流行病学--线粒体遗传

• 批准号: 6618256
• 负责人: GEORGE F WOOTEN
• 金额: $ 23.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6618256
• 关键词: Parkinson's disease; clinical research; disease /disorder etiology; disease /disorder onset; electron transport; family genetics; gender difference; gene mutation; genetic disorder; genetic susceptibility; human genetic material tag; human subject; mitochondrial DNA; nervous system disorder epidemiology; neurogenetics; pathologic process; respiratory enzyme; siblings

The main scientific theme of this project is to determine if the genetic epidemiology of Parkinson's disease (PD) is consistent with an etiologic role for inherited abnormalities of mitochondrial DNA (mtDNA). The presence of a mitochondrial complex I defect in subjects with PD is now well established. Furthermore, this defect appears to arise as a consequence of abnormalities in mtDNA. Whether these abnormalities of mtDNA are acquired or inherited is not known, but we have recently shown in a multi-generational family with PD in which transmission has been exclusively along maternal lines that maternal offspring have lower Complex I activity than paternal offspring. In Project 3 we will use data on family history of PD in PD subjects and controls generated by the Subject Accrual and Ascertainment component of the Core. These data will be examined to test three hypotheses regarding the role of mtDNA mutations in particular, and genetic risk factors in general, in the etiology of PD. Hypothesis 1: There is a predominance of maternal inheritance in PD. If inherited mtDNA mutations play a role in PD etiology, one would predict an excess of maternal inheritance. We will compare directly the number of affected mothers and fathers of probands using survival analysis. Logistic regression will be used to evaluate the influence of the gender of affected parents when probands have both an affected sibling and an affected parent, and to determine the relative risk of developing PD between PD subjects and controls when there is an affected mother versus an affected father. Hypothesis 2: Parkinson's disease susceptibility is determined by a major gene. We will perform a complex segregation analysis of a series of consecutively ascertained nuclear genetic families. Hypothesis 3: Certain disease characteristics of PD may be associated with familial or non-familial PD. Using logistic regression and analysis of variance, we will address the question of whether early age of onset, gender, or rapid symptom progression in PD is associated with a positive family history.

该项目的主要科学主题是确定帕金森氏病（PD）的遗传流行病学是否与线粒体DNA（MTDNA）遗传异常的病因作用一致。现在已经确定了PD受试者中线粒体复合物I缺陷的存在。此外，由于mtDNA异常，这种缺陷似乎是出现的。是否获取或遗传了mtDNA的这些异常是不知道的，但是我们最近在具有PD的多代家族中表明，与父亲后代相比，母体后代的复杂I活性仅沿着母体线沿着母体线延伸。在项目3中，我们将使用有关PD主题中PD家族史的数据以及由核心的应计和确定成分产生的对照。将检查这些数据，以检验有关mtDNA突变的作用，概念上的遗传风险因素在PD病因中的三个假设。假设1：PD中母亲的遗传占主导地位。如果遗传的mtDNA突变在PD病因中起作用，则可以预测过多的母体遗传。我们将使用生存分析直接比较受影响的母亲和父亲的数量。逻辑回归将用于评估受影响父母的性别的影响，当概率既有受影响的兄弟姐妹又是受影响的父母，并确定当患有受影响的母亲而不是受影响的父亲时，在PD受试者和对照之间发展PD的相对风险。假设2：帕金森氏病敏感性由主要基因决定。我们将对一系列连续确定的核遗传家族进行复杂的隔离分析。假设3：PD的某些疾病特征可能与家族性或非家庭PD有关。使用逻辑回归和方差分析，我们将解决PD发病，性别或快速症状进展的问题是否与积极的家族史有关。