GENETIC EPIDEMIOLOGY OF PD--MITOCHONDRIAL INHERITANCE

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遗传性异常(MtDNA)的病因学作用一致。帕金森病患者中存在线粒体复合体I缺陷，这一点现已得到证实。此外，这种缺陷似乎是线粒体DNA异常的结果。MtDNA的这些异常是后天的还是遗传的尚不清楚，但我们最近在一个多代帕金森病患者家庭中发现，母亲的后代比父亲的后代具有更低的复杂I活性。在项目3中，我们将使用核心的科目应计和确定部分生成的帕金森病受试者和对照的帕金森病家族史数据。这些数据将被用来检验关于线粒体DNA突变在帕金森病病因中的作用的三个假说，特别是遗传风险因素。假设1：帕金森病以母系遗传为主。如果遗传性mtDNA突变在帕金森病的病因中起作用，人们将预测母系遗传过量。我们将使用生存分析直接比较受影响的先证者母亲和父亲的数量。Logistic回归将用于评估先证者既有受影响的兄弟姐妹又有受影响的父母时受影响父母的性别的影响，以及当有受影响的母亲和受影响的父亲时，帕金森病受试者和对照组之间发生帕金森病的相对风险。假设2：帕金森氏症的易感性由一个主基因决定。我们将对一系列连续确定的核心基因家族进行复杂的分离分析。假设3：帕金森病的某些疾病特征可能与家族性或非家族性帕金森病有关。运用Logistic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。

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.