Molecular Neurology, Research Program Unit, Biomedicum, University of Helsinki Helsinki, Finland.
Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB Helsinki, Finland ; Folkhalsan Institute of Genetics Helsinki, Finland.
Ann Clin Transl Neurol. 2015 Sep;2(9):920-31. doi: 10.1002/acn3.231. Epub 2015 Aug 18.
Dementia with Lewy bodies is an α-synucleinopathy characterized by neocortical Lewy-related pathology (LRP). We carried out a genome-wide association study (GWAS) on neocortical LRP in a population-based sample of subjects aged 85 or over.
LRP was analyzed in 304 subjects in the Vantaa 85+ sample from Southern Finland. The GWAS included 41 cases with midbrain, hippocampal, and neocortical LRP and 177 controls without midbrain and hippocampal LRP. The Medical Research Council Cognitive Function and Ageing Study (CFAS) material was used for replication (51 cases and 131 controls).
By analyzing 327,010 markers the top signal was obtained at the HLA-DPA1/DPB1 locus (P = 1.29 × 10(-7)); five other loci on chromosomes 15q14, 2p21, 2q31, 18p11, and 5q23 were associated with neocortical LRP at P < 10(-5). Two loci were marked by multiple markers, 2p21 (P = 3.9 × 10(-6), upstream of the SPTBN1 gene), and HLA-DPA1/DPB1; these were tested in the CFAS material. Single marker (P = 0.0035) and haplotype (P = 0.04) associations on 2p21 were replicated in CFAS, whereas HLA-DPA1/DPB1 association was not. Bioinformatic analyses suggest functional effects for the HLA-DPA1/DPB1 markers as well as the 15q14 marker rs8037309.
We identified suggestive novel risk factors for neocortical LRP. SPTBN1 is the candidate on 2p21, it encodes beta-spectrin, an α-synuclein binding protein and a component of Lewy bodies. The HLA-DPA1/DPB1 association suggests a role for antigen presentation or alternatively, cis-regulatory effects, one of the regulated neighboring genes identified here (vacuolar protein sorting 52) plays a role in vesicular trafficking and has been shown to interact with α-synuclein in a yeast model.
路易体痴呆是一种以α-突触核蛋白病为特征的疾病，其特点是新皮质路易相关病理学（LRP）。我们在一个基于人群的 85 岁或以上受试者样本中进行了新皮质 LRP 的全基因组关联研究（GWAS）。
在芬兰南部的万塔 85+样本中，对 304 名受试者进行了 LRP 分析。GWAS 包括 41 例中脑、海马和新皮质 LRP 病例和 177 例无中脑和海马 LRP 对照。使用医学研究委员会认知功能与衰老研究（CFAS）材料进行复制（51 例和 131 例对照）。
通过分析 327010 个标记物，在 HLA-DPA1/DPB1 基因座获得了最高信号（P=1.29×10(-7)）；在染色体 15q14、2p21、2q31、18p11 和 5q23 上的另外五个位点与新皮质 LRP 相关，P<10(-5)。两个位点被多个标记物标记，2p21（P=3.9×10(-6)，位于 SPTBN1 基因的上游）和 HLA-DPA1/DPB1；这些在 CFAS 材料中进行了测试。在 CFAS 中，2p21 上的单标记物（P=0.0035）和单倍型（P=0.04）关联得到复制，而 HLA-DPA1/DPB1 关联则没有。生物信息学分析表明，HLA-DPA1/DPB1 标记物以及 15q14 标记物 rs8037309 具有功能效应。
我们确定了新皮质 LRP 的提示性新危险因素。SPTBN1 是 2p21 上的候选基因，它编码β- spectrin，这是一种α-突触核蛋白结合蛋白，也是路易体的组成部分。HLA-DPA1/DPB1 的关联表明抗原呈递或顺式调控效应的作用，这里鉴定的一个受调控的邻近基因（液泡蛋白分选 52）在囊泡运输中起作用，并在酵母模型中显示与α-突触核蛋白相互作用。
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