Mapping a Gene for Parkinsons Disease in Norway

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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.