Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.
Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.
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DOI：
10.1007/s00439-016-1638-x
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发表时间：
2016-04
期刊：
影响因子：
5.3
通讯作者：
Reinders MJT
中科院分区：
文献类型：
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作者：
Eising E;Huisman SMH;Mahfouz A;Vijfhuizen LS;Anttila V;Winsvold BS;Kurth T;Ikram MA;Freilinger T;Kaprio J;Boomsma DI;van Duijn CM;Järvelin MR;Zwart JA;Quaye L;Strachan DP;Kubisch C;Dichgans M;Davey Smith G;Stefansson K;Palotie A;Chasman DI;Ferrari MD;Terwindt GM;de Vries B;Nyholt DR;Lelieveldt BPF;van den Maagdenberg AMJM;Reinders MJT
偏头痛是一种常见的致残性神经血管性脑疾病，其典型特征是剧烈头痛发作，并伴有自主神经系统症状。偏头痛是由遗传和环境因素的相互作用引起的。全基因组关联研究（GWAS）已经确定了十多个与偏头痛相关的基因位点。在这里，我们将偏头痛GWAS数据与来自Allen人脑图谱的正常成人大脑的高分辨率空间基因表达数据相结合，以确定可能参与偏头痛病理生理的特定大脑区域和分子通路。为此，我们采用了两种互补的方法。在23,285例偏头痛患者和95,425例对照组的GWAS数据中，我们首先研究了基于人脑表达数据计算的共表达基因模块，以富集与偏头痛相关的基因。偏头痛GWAS信号的富集在5个模块中被发现，这些模块可能参与偏头痛的病理生理：(i)皮层中的神经传递、蛋白质分解代谢和线粒体；（ii）皮层和小脑的转录调控；（iii）皮质下区域的少突胶质细胞和线粒体。其次，我们利用偏头痛GWAS的高置信度基因作为基础，构建局部偏头痛相关的共表达基因网络。在第一种方法中突出的所有大脑区域和通路的特征也在第二种方法中出现，从而支持这些大脑区域和通路确实参与了偏头痛的病理生理。本文的在线版本（doi:10.1007/s00439-016-1638-x）包含补充材料，仅供授权用户使用。
Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology. The online version of this article (doi:10.1007/s00439-016-1638-x) contains supplementary material, which is available to authorized users.