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Mol Psychiatry:北京大学马弘、于欣教授研究组发表精神分裂症遗传学研究进展

摘要 : 2016年1月5日,国际学术权威刊物自然出版集团旗下子刊、精神病学著名杂志《Molecular Psychiatry》在线发表北京大学医学部附属第六医院马弘主任医师与于欣教授的研究团队与国内外15家机构合作的研究论文

 

2016年1月5日,国际学术权威刊物自然出版集团旗下子刊、精神病学著名杂志《Molecular Psychiatry》在线发表北京大学医学部附属第六医院马弘主任医师与于欣教授的研究团队与国内外15家机构合作的研究论文,研究基于社区精神卫生服务网络开展了一项精神分裂症遗传学研究。研究题为“17q25常见变异及其基因-基因交互作用增加精神分裂症患病风险并调节人脑中的基因表达”。

这项研究始于2012年,首先采用独立的病例-对照样本对已发表的两项中国汉族人群精神分裂症全基因组关联研究的主要结果进行了独立验证,发现两个常见单核苷酸多态性位点存在显著的交互作用,且能增加精神分裂症的患病风险。这两个位点分别位于微管蛋白折叠辅因子D基因(TBCD)内含子和锌指蛋白750基因(ZNF750)第2外显子的5'非翻译区,均坐落于17q25上,该染色体区域是精神分裂症遗传学研究的热点区域之一。随后,课题组利用基因型-组织表达数据探索了这两个位点的不同基因型组合与人脑组织中13个区域基因表达的关系,发现皮质中TEAD3、SH3TC2、KCNK9和PPDPF表达水平,以及小脑中EFNA1、RNU4ATAC和NUPL2表达水平受到两个位点之间交互作用的调节。

这项研究首次提示TBCD和ZNF750两个基因增加精神分裂症的易感性,并首次发现这两个基因与人类大脑组织中的基因转录水平有关,增进了对精神分裂症病因学的理解。

原文链接:

Common variants on 17q25 and gene–gene interactions conferring risk of schizophrenia in Han Chinese population and regulating gene expressions in human brain

原文摘要:

Recently, two genome-wide association studies (GWASs) of schizophrenia (SCZ) in Han Chinese identified several susceptibility loci. Replication efforts aiming to validate the GWAS findings were made and focused on the top hits. We conducted a more extensive follow-up study in an independent sample of 1471 cases and 1528 matched controls to verify 26 genetic variants by including nine top single-nucleotide polymorphisms (SNPs) that reached genome-wide significance and 17 promising SNPs nominated in the initial discovery phase. rs8073471 in an intron of tubulin-folding cofactor D (TBCD) obtained nominal significance (P<0.01) in single SNP analysis. Logistic regression identified significant interaction between rs3744165 (5’-untranslated region variant of exon 2 of zinc finger protein 750 (ZNF750), and in an intron of TBCD) and rs8073471 (Deviance test P-value=2.77 × 10−34). Both SNPs are located at 17q25, an interesting region that has been implicated in SCZ. By using the Genotype-Tissue expression (GTEx) data set, we implemented an expression quantitative trait loci epistasis analysis to explore the association between the genotype combinations of the two SNPs and gene expression levels in 13 areas of human central nervous system. We observed that rs3744165 × rs8073471 interaction modulated the expression profile of TEAD3 (P=1.87 × 10−8), SH3TC2 (P=2.00 × 10−8), KCNK9 (P=5.20 × 10−7) and PPDPF (P=1.13 × 10−6) in postmortem cortex tissue; EFNA1 (P=7.26 × 10−9), RNU4ATAC (P=2.32 × 10−8) and NUPL2 (P=6.79 × 10−8) in cerebellum tissue. To the best of our knowledge, our study is the first one that links TBCD and ZNF750 mutations to SCZ susceptibility and to the transcript levels in human brain tissues. Further efforts are needed to understand the role of those variants in the pathogenesis of SCZ.

来源: Molecular Psychiatry 浏览次数:0

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