Mapping a Gene for Parkinsons Disease in Norway

描述（由申请人提供）：人类基因组的9个区域（park1 -9）与帕金森病的遗传有关，其中大多数与小常染色体显性或隐性谱系的血统定位有关。这些家庭中的突变，虽然阐明了受影响的潜在遗传途径，但可能仅在少数情况下是因果关系。最近，在冰岛人群中，1p32上的一个位点PARK 10与常见的晚发性帕金森病（PD）有关（LOD=4.9）。为了支持这项研究，我们利用受影响的兄弟姐妹对，在美国人群中发现了影响帕金森病患者年龄的重叠1p32位点（LOD =3.41）。这些序列直接重叠，跨越6.75cM （Iod -1连锁区间），大约有720万个碱基和许多候选基因。人口历史和基因数据告诉我们，冰岛的遗产主要是北欧血统。因此，我们的建议是利用挪威人群中的祖先重组事件进行更高分辨率的遗传作图。我们打算使用单核苷酸多态性（snp）来评估1p32的连锁不平衡（LD）模式（目的1）。我们的初步分析表明，在挪威PD病例中，广泛的1p32 LD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聚结模型来确定pd易感性变异的位置，并优先考虑候选基因分析（目标2）。正如在冰岛和美国人群中一样，我们假设1p32变异将与挪威人群的PD有关。虽然PD是一种复杂的特征，但我们假设挪威病例起源于相对同质的分离，在关联映射方面将比美国PD病例更强大。我们将探索单倍型标记（htsnp）捕获疾病关联的效用（目标3）。pd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.