A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression.
A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression.
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DOI：
10.1016/j.jalz.2015.05.011
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Chiba-Falek O
中科院分区：
文献类型：
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作者：
Lutz MW;Saul R;Linnertz C;Glenn OC;Roses AD;Chiba-Falek O
我们最近发现，在AD病例中，SNCA基因座上的标记SNP与LB病理风险增加显著相关。然而，作为观察到的关联基础的实际遗传变异仍然难以捉摸。我们使用生物信息学算法对SNCA-内含子4区域中的结构变体进行编目，然后进行分相测序。我们对LBV/AD病例的尸检系列与AD对照组进行了遗传关联分析。我们使用颞叶皮层样本通过表达分析来研究其生物学功能。我们确定了四个不同的单倍型内的高度多态性低复杂性CT丰富的区域。我们发现，一个特定的单倍型赋予发展LBV/AD的风险。我们证明了富含CT的位点作为增强子元件，其中风险单倍型与SNCA-mRNA水平升高显著相关。我们在SNCA富含CT的区域发现了一种新的单倍型，该单倍型可能通过基因表达的顺式调节导致AD患者的LB病理。
We recently showed that tagging-SNPs across the SNCA locus were significantly associated with increased risk for LB pathology in AD cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive. We used a bioinformatics algorithm to catalogue Structural-Variants in a region of SNCA-intron4, followed by phased-sequencing. We performed a genetic-association analysis in autopsy series of LBV/AD cases compared with AD-only controls. We investigated the biological functions by expression analysis using temporal-cortex samples. We identified four distinct haplotypes within a highly-polymorphic-low-complexity CT-rich region. We showed that a specific haplotype conferred risk to develop LBV/AD. We demonstrated that the CT-rich site acts as an enhancer element, where the risk haplotype was significantly associated with elevated levels of SNCA-mRNA. We have discovered a novel haplotype in a CT-rich region in SNCA that contributes to LB pathology in AD patients, possibly via cis-regulation of the gene expression.