GENETIC EPIDEMIOLOGY OF PD--MITOCHONDRIAL INHERITANCE

PD遗传流行病学--线粒体遗传

• 批准号: 6664102
• 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/6664102
• 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病（PD）的遗传流行病学是否与线粒体DNA （mtDNA）遗传异常的病因学作用一致。帕金森病患者线粒体复合体I缺陷的存在现已得到充分证实。此外，这种缺陷似乎是mtDNA异常的结果。这些mtDNA异常是获得性还是遗传性尚不清楚，但我们最近在一个多代PD家族中发现，在该家族中，遗传仅沿母系进行，母系后代的Complex I活性低于父系后代。在项目3中，我们将使用PD受试者和对照的PD家族史数据，这些数据由核心的受试者应计和确定部分生成。这些数据将检验三个假设，特别是关于mtDNA突变的作用，以及遗传风险因素，在PD的病因学中。假设1:PD存在母体遗传优势。如果遗传mtDNA突变在PD病因学中起作用，可以预测母体遗传过多。我们将使用生存分析直接比较先证者受影响的母亲和父亲的数量。Logistic回归将用于评估先证者同时有患病兄弟姐妹和患病父母时，患病父母性别的影响，并确定当有患病母亲与有患病父亲时，PD受试者与对照组之间发生PD的相对风险。假设2：帕金森病易感性是由一个主要基因决定的。我们将对一系列连续确定的核遗传家族进行复杂的分离分析。假设3:PD的某些疾病特征可能与家族性或非家族性PD有关。使用逻辑回归和方差分析，我们将探讨帕金森病的早期发病年龄、性别或症状快速进展是否与阳性家族史相关。