Genetic Analysis Of Non-alzheimer Dementias

在这一年里，我们发现了几个有颗粒蛋白前突变的家族，现在已经发表了关于这方面的论文。这项工作表明，颗粒蛋白前突变产生相当典型的表型，与肌萎缩性侧索硬化症等重叠疾病无关。我们使用密集的基于SNP的连锁图谱来识别与家族性额颞叶痴呆相关的新位点。这项工作显示了9号染色体上现存位点的连锁重叠，我们现在参与了一个定位克隆项目，以确定这个家族的潜在基因突变；该项目涉及在临界间隔内对大约80个基因进行测序，目前已完成50%。

During this year we have found several families with progranulin mutations and now have papers published and in press on this. This work has shown that progranulin mutations produce a fairly typical phenotype and are not associated with overlapping disorders such as amyotrophic lateral sclerosis. We have used dense SNP based linkage mapping to identify novel loci associated with familial frontotemporal dementia. This work shows linkage overlapping an extant locus on chromosome 9 and we are now involved in a positional cloning project to determine the underlying genetic mutation in this family; this project involves sequencing of approximately 80 genes within the critical interval and is currently 50% complete. Our ongoing work on dementia with Lewy bodies and Parkinson's disease with dementia primarily focuses on analysis of loci identified in our genome wide association studies in Alzheimer's disease and Parkinson's disease to see if we can tease out the genetic basis of dementia in these disorders which neuropathologically sit between Alzheimer's and Parkinson's disease. This work complements our analysis of quantitative neuropathology in a series of brains from a longitudinal aging study from Finland; in particular the analysis of these neuropathological measures in terms of genetic risk - we have performed quantitative trait locus mapping in approximately 250 such brains and identified several loci positively associated with amyloid, tau and synuclein pathologies.