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。现已明确，帕金森病患者存在线粒体复合物 I 缺陷。此外，这种缺陷似乎是线粒体 DNA 异常的结果。这些 mtDNA 异常是获得性的还是遗传性的尚不清楚，但我们最近在一个患有 PD 的多代家庭中发现，在该家庭中，仅沿着母系传播，母系后代的复合物 I 活性低于父系后代。在项目 3 中，我们将使用 PD 受试者中的 PD 家族史数据以及由核心的受试者应计和确定组件生成的控制。将检查这些数据，以检验关于 mtDNA 突变在 PD 病因学中的作用以及一般遗传风险因素的三个假设。假设1：PD 中母系遗传占主导地位。如果遗传性 mtDNA 突变在 PD 病因学中发挥作用，则可以预测母系遗传过多。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。当先证者同时有受影响的兄弟姐妹和受影响的父母时，Logistic 回归将用于评估受影响父母的性别的影响，并确定当有受影响的母亲与受影响的父亲时，确定 PD 受试者和对照之间发生 PD 的相对风险。假设2：帕金森病的易感性由主基因决定。我们将对一系列连续确定的核心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 相关。使用逻辑回归和方差分析，我们将解决 PD 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的问题。