Genetic Linkage Study in Parkinson's Disease

描述(申请人提供)：特发性帕金森病(PD)的病因，a 据估计，在60岁或以上的人中，有1%患有衰弱疾病，目前尚不清楚。在这一应用中，我们提出了PD的遗传流行病学研究、遗传连锁研究和候选基因研究。在过去的四年里，我们建立了一个多机构的研究计划，收集了300对受帕金森病影响的兄弟姐妹和大家庭。我们对发病年龄的连锁分析显示，有证据表明染色体2pl3在‘Park3’位点上存在连锁(LOD 2.1)(Gasser等人)。1998年)。最近，我们发现了与Gasser博士团队相同的STR标记和等位基因的关联(p&lt；0.02)，以及与SNP等位基因的关联(pC0.008)。我们还发现了与其他团队报告的另外两个基因座关联的证据。我们所报道的与9q号染色体上的帕金森病相关(DeStefano等人)。2001)也是由Scott等人报道的。(2001年)。梅奥诊所杰克逊维尔的哈迪博士和法雷尔博士证实，在我们报道的帕金森氏病影响的同一区域，染色体10q存在连锁。因此，我们已经检测到至少三个区域(2p、9q和10q)包含其他组检测到的PD相关基因。这些发现证实了帕金森病是一个复杂的特征，需要大量具有良好特征的样本来足够的能力来识别相关基因。我们提出(目的1)遗传流行病学研究，旨在通过研究预测发病年龄的危险因素来确定与帕金森病外显相关的因素，这些危险因素对发病年龄有很大的不同。这种独特的兄弟姐妹对样本允许对与外显性相关的因素进行新颖的分析。我们建议(目标2)继续我们的遗传连锁分析，对350对受影响的兄弟姐妹和其他家庭成员进行10 cM密度基因组扫描；已经收集了300对受影响的兄弟姐妹对。我们将评估与危险因素参与和帕金森病家族史相关的可能的遗传异质性。我们发现了发病年龄的显著改变。我们建议(目标4)跟踪那些有证据表明与帕金森病或发病年龄相关的区域，并在这项研究中收集另外350对帕金森病同胞。我们进一步建议进行关联研究，以定位候选基因。最后，我们建议(目的5)帕金森病候选基因研究，主要集中在与肌张力障碍有关的基因和基因组区域，因为帕金森病和肌张力障碍的临床特征重叠。该项目具有极大的潜力来扩大我们对帕金森病遗传学的认识，并识别帕金森病相关基因及其相互作用的危险因素和模式。

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.