Mapping a Gene for Parkinsons Disease in Norway

描述(由申请人提供)：人类基因组的九个区域(PARK1-9)与帕金森氏症的遗传学有关，其中大多数涉及小型常染色体显性或隐性家系中的身份-血统映射。在阐明受影响的潜在遗传途径的同时，这些家族中的突变很可能只在少数情况下是因果关系。最近，位于1p32上的Park 10基因与冰岛人群中常见的晚发型帕金森病(PD)有关(LOD=4.9)。支持这一分配的是，在美国人群中，使用受影响的同胞对(LOD=3.41)将影响帕金森病患者年龄的重叠的1p32基因座联系在一起。这些区间直接重叠，跨越6.75cM(IoD-1连锁区间)，约720万个碱基和众多候选基因。人口历史和基因数据告诉我们，冰岛的遗产主要是北欧后裔。因此，我们的建议是利用挪威人口中的祖先重组事件来进行更高分辨率的基因图谱绘制。我们打算使用单核苷酸多态(SNPs)来评估跨越1p32(目标1)的连锁不平衡(LD)模式。我们的初步分析表明，在挪威帕金森病患者中，存在广泛的1p32LD和祖先单倍型的保存。随后，我们将使用单倍型关联分析和多点联合建模来精炼PD易感变异的位置，并优先进行候选基因分析(目标2)。正如在冰岛和美国人群中一样，我们假设1p32变异与挪威人群中的帕金森病有关。虽然帕金森病是一个复杂的特征，但我们假设挪威病例起源于一个相对同质的分离株，在关联图谱方面将比美国帕金森病病例更强大。我们将探索单倍型标签(HtSNPs)用于捕获疾病关联的效用(目标3)。帕金森病易感基因的鉴定将在美国样本中得到确认，并进行功能评估。

DESCRIPTION (provided by applicant): Nine regions of the human genome (PARK 1-9) have been implicated in the genetics of parkinsonism, the majority implicated by identity-by-descent mapping in small autosomal dominant or recessive pedigrees. Mutations in these families, while elucidating the underlying genetic pathway affected are likely to be causal in only a small number of cases. More recently, PARK 10 a locus on 1p32, was linked to common, late-onset Parkinson's disease (PD) in the Icelandic population (LOD=4.9). Supporting this assignment, an overlapping 1p32 locus influencing age of PD cases was linked in the US population using affected sib-pairs (LOD =3.41). The intervals directly overlap, spanning 6.75cM (Iod -1 linked interval), approximately 7.2 million bases and numerous candidate genes. Population history and genetic data tells us that Iceland's heritage is primarily of Norse descent. Hence, our proposal is to exploit ancestral recombination events in the Norwegian population for higher-resolution genetic mapping. We intend to use single nucleotide polymorphisms (SNPs) to assess the pattern of linkage disequilibrium (LD) across 1p32 (Aim 1). Our preliminary analysis demonstrates extensive 1p32 LD and conservation of ancestral haplotypes, in Norwegian PD cases. We will subsequently use haplotype association analyses and multipoint coalescent modeling to refine the location of the PD-susceptibility variant and prioritize candidate gene analysis (Aim 2). As in the Icelandic and US populations, we hypothesize 1p32 variability will be associated with PD in the Norwegian population. Although PD is a complex trait, we postulate Norwegian cases, originating from a relatively homogeneous isolate, will be more powerful than US PD cases for association mapping. We will explore the utility of haplotype tagging (htSNPs) to capture disease-association (Aim 3). Identification of the PD-susceptibility gene will be confirmed in US samples and functionally assessed.