Mapping a Gene for Parkinsons Disease in Norway

挪威帕金森病基因图谱绘制

• 批准号: 6943502
• 负责人: MATTHEW J FARRER
• 金额: $ 38.5万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943502
• 关键词: Parkinson' s disease; Scandinavian country; clinical research; family genetics; genetic mapping; genetic susceptibility; human subject; linkage disequilibriums; single nucleotide polymorphism

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.

描述（由申请人提供）：人类基因组的九个区域（PARK 1-9）与帕金森症的遗传学有关，其中大部分与小型常染色体显性或隐性谱系中的血统身份图谱有关。 这些家族的突变虽然阐明了受影响的潜在遗传途径，但可能仅在少数病例中具有因果关系。最近，1p32 上的 PARK 10 基因座与冰岛人群中常见的迟发性帕金森病 (PD) 相关 (LOD=4.9)。 支持这一分配的是，使用受影响的同胞对在美国人群中将影响 PD 病例年龄的重叠 1p32 位点关联起来 (LOD = 3.41)。这些区间直接重叠，跨越6.75cM（Iod -1连锁区间），大约720万个碱基和众多候选基因。 人口历史和遗传数据告诉我们，冰岛的血统主要是北欧血统。 因此，我们的建议是利用挪威人群的祖先重组事件来进行更高分辨率的遗传图谱。我们打算使用单核苷酸多态性 (SNP) 来评估 1p32 上的连锁不平衡 (LD) 模式（目标 1）。我们的初步分析表明，在挪威 PD 病例中存在广泛的 1p32 LD 和祖先单倍型的保守性。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 易感性变异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 1p32 变异与挪威人群的 PD 相关。尽管PD是一种复杂的特征，但我们假设源自相对同质的隔离株的挪威病例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) 在捕获疾病关联方面的效用（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。