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（PARK 1-9）与帕金森综合征的遗传学有关，大多数与小型常染色体显性或隐性家系中的血统同一性作图有关。 这些家族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，PARK 10（1 p32上的一个位点）与冰岛人群中常见的迟发性帕金森病（PD）有关（LOD=4.9）。 支持这一分配，在美国人群中使用受影响的同胞对（LOD =3.41）关联了影响PD病例年龄的重叠1 p32基因座。区间直接重叠，跨越6.75cM（IOd-1连锁区间），约720万个碱基和许多候选基因。 人口历史和遗传数据告诉我们，冰岛的遗产主要是北欧血统。 因此，我们的建议是利用祖先的重组事件在挪威人口的高分辨率遗传图谱。我们打算使用单核苷酸多态性（SNPs）来评估1 p32（Aim 1）的连锁不平衡（LD）模式。我们的初步分析表明，广泛的1 p32 LD和保护祖先单倍型，在挪威PD病例。随后，我们将使用单倍型关联分析和多点合并建模来细化PD易感性变体的位置，并优先考虑候选基因分析（目标2）。与冰岛和美国人群一样，我们假设1 p32变异性与挪威人群的PD相关。虽然PD是一个复杂的特征，我们假设挪威的情况下，从一个相对同质的隔离，将比美国PD的情况下，关联映射更强大。我们将探索单倍型标签（htSNPs）捕获疾病相关性（目的3）的效用。将在US样本中确认PD易感基因的鉴定并进行功能评估。

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.