Ferrari Raffaele, Ryten Mina, Simone Roberto, Trabzuni Daniah, Nicolaou Nayia, Hondhamuni Geshanthi, Ramasamy Adaikalavan, Vandrovcova Jana, Weale Michael E, Lees Andrew J, Momeni Parastoo, Hardy John, de Silva Rohan
Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Neurobiol Aging. 2014 Jun;35(6):1514.e1-12. doi: 10.1016/j.neurobiolaging.2014.01.010. Epub 2014 Jan 13.
Progressive supranuclear palsy is a rare parkinsonian disorder with characteristic neurofibrillary pathology consisting of hyperphosphorylated tau protein. Common variation defining the microtubule associated protein tau gene (MAPT) H1 haplotype strongly contributes to disease risk. A recent genome-wide association study (GWAS) revealed 3 novel risk loci on chromosomes 1, 2, and 3 that primarily implicate STX6, EIF2AK3, and MOBP, respectively. Genetic associations, however, rarely lead to direct identification of the relevant functional allele. More often, they are in linkage disequilibrium with the causative polymorphism(s) that could be a coding change or affect gene expression regulatory motifs. To identify any such changes, we sequenced all coding exons of those genes directly implicated by the associations in progressive supranuclear palsy cases and analyzed regional gene expression data from control brains to identify expression quantitative trait loci within 1 Mb of the risk loci. Although we did not find any coding variants underlying the associations, GWAS-associated single-nucleotide polymorphisms at these loci are in complete linkage disequilibrium with haplotypes that completely overlap with the respective genes. Although implication of EIF2AK3 and MOBP could not be fully assessed, we show that the GWAS single-nucleotide polymorphism rs1411478 (STX6) is a strong expression quantitative trait locus with significantly lower expression of STX6 in white matter in carriers of the risk allele.
进行性核上性麻痹是一种罕见的帕金森氏症，具有由高度磷酸化的tau蛋白组成的特征性神经原纤维病理改变。定义微管相关蛋白tau基因（MAPT）H1单倍型的常见变异对疾病风险有很大影响。最近的一项全基因组关联研究（GWAS）在1号、2号和3号染色体上发现了3个新的风险位点，分别主要涉及STX6、EIF2AK3和MOBP。然而，基因关联很少能直接确定相关的功能等位基因。更常见的情况是，它们与可能是编码改变或影响基因表达调控基序的致病多态性处于连锁不平衡状态。为了识别任何此类变化，我们对进行性核上性麻痹病例中关联直接涉及的那些基因的所有编码外显子进行了测序，并分析了来自对照大脑的区域基因表达数据，以识别风险位点1 Mb范围内的表达数量性状位点。尽管我们没有发现这些关联背后的任何编码变异，但这些位点上与GWAS相关的单核苷酸多态性与与各自基因完全重叠的单倍型处于完全连锁不平衡状态。尽管无法全面评估EIF2AK3和MOBP的影响，但我们表明GWAS单核苷酸多态性rs1411478（STX6）是一个强大的表达数量性状位点，在风险等位基因携带者的白质中STX6的表达显著降低。
