Genetic Linkage Study in Parkinson's Disease

描述（由申请人提供）：特发性帕金森病（PD）的原因， 据估计，有1%的60岁或60岁以上的人患有这种使人衰弱的疾病，但目前还不清楚。在这个应用程序中，我们提出遗传流行病学研究，遗传连锁研究，和候选基因的PD研究。在过去的四年里，我们已经建立了一个多机构的研究计划，收集了300 PD影响的兄弟姐妹对和大家庭。我们对发病年龄的连锁分析揭示了在“PARK 3”基因座处与染色体2 p13连锁（LOD 2.1）的证据（Gasser等，1998）。最近，我们发现了与Gasser博士的研究小组所观察到的相同STR标记和等位基因的关联（p<0.02）以及与SNP等位基因的关联（p <0.008）。我们还看到了与其他研究小组报告的其他两个基因座连锁的证据。Scott et al.（2001）也报告了我们报告的与染色体9 q上PD影响的关联（DeStefano et al. 2001）。杰克逊维尔马约诊所的哈代和法雷尔博士证实了与我们报道的PD感染相同区域的染色体10 q的连锁。因此，我们已经检测到至少三个区域（2 p，9 q和10 q）含有其他组检测到的PD相关基因。这些发现证实了PD是一种复杂的性状，需要大量表征良好的样本才有足够的能力来识别相关基因。 我们提出（AIM 1）遗传流行病学研究，旨在通过研究预测发病年龄广泛不一致的兄弟姐妹对的发病年龄的风险因素来确定与PD外显率相关的因素。这种独特的兄弟姐妹对样本允许新的分析因素有关的aberrance。我们建议（AIM 2）继续我们的遗传连锁分析，在350个受影响的同胞对和其他家庭成员中进行10 cM密度的基因组扫描;已经收集了300个受影响的同胞对。我们将评估与危险因素参与和PD家族史相关的可能遗传异质性。我们发现发病年龄有显著变化。我们建议（AIM 4）随访那些与PD影响或发病年龄相关的区域，并在本研究中收集额外的350个PD同胞对。我们进一步提出关联研究定位候选基因。最后，我们提出（AIM 5）一个集中的候选基因研究PD，主要集中在基因和基因组区域涉及肌张力障碍，由于重叠的临床特征PD和肌张力障碍。该项目具有很大的潜力，以扩大我们的知识，遗传学的PD和确定PD相关基因和危险因素和模式的相互作用。

DESCRIPTION (provided by applicant): The cause of idiopathic Parkinson's disease (PD), a debilitating disease that afflicts an estimated 1 percent of persons age 60 or older, remains unknown. In this application, we propose genetic epidemiological studies, genetic linkage studies, and candidate gene studies for PD. In the past four years, we have established a ulti-institutional research program that has collected 300 PD affected sibling pairs and extended families. Our linkage analyses to onset age revealed evidence for linkage (LOD 2.1) to chromosome 2pl3 at the 'PARK3' locus (Gasser et al. 1998). Recently, we found association (p<0.02) to the same STR marker and allele as seen by Dr. Gasser's group and association to SNP alleles (pC0.008) We also see evidence for linkage to two other loci reported by other groups. Our reported linkage to PD affection on chromosome 9q (DeStefano et al. 2001) is also reported by Scott et al. (2001). Drs. Hardy and Farrer of the Mayo Clinic Jacksonville confirm linkage to chromosome 10q in the same region that we reported for PD affection. Thus, we have detected at least three regions (2p, 9q, and 10q) that harbor PD related genes detected by other groups. These findings confirm that PD is a complex trait, requiring a large well-characterized sample for sufficient power to identify the implicated genes. We propose (AIM 1) genetic epidemiological studies aimed at identifying factors related to penetrance in PD by studying risk factors predicting onset age in sibling pairs who are widely discordant for onset age. This unique sample of sibling pairs permits novel analyses of factors related to penetrance. We propose (AIM 2) to continue our genetic linkage analysis, with a 10cM density genome scan in 350 affected sibling pairs and other family members; 300 of these affected sibling pairs have already been collected. We will assess possible genetic heterogeneity associated with risk factor involvement and PD family history. We have found significant modification of onset age. We propose (AIM 4) to follow-up those regions with evidence for linkage to PD affection or onset age in and additional 350 PD sib pairs to be collected in this study. We further propose association studies to localize candidate genes. Finally, we propose (AIM 5) a focused candidate gene study for PD, concentrating primarily on genes and genomic regions implicated in dystonia, due to overlapping clinical features of PD and dystonia. This project has great potential to expand our knowledge of the genetics of PD and to identify PD associated genes and risk factors and patterns for their interaction.