Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant ...Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.展开更多
背景近年来,众多研究报导了数百种与焦虑症有关的基因,为系统研究焦虑症的基因网络提供了研究基础。方法从Res Net 11 Mammalian数据库中提取了焦虑症-基因的关系数据,包含592个焦虑症基因。通过基因富集分析、子网络富集分析、网络连...背景近年来,众多研究报导了数百种与焦虑症有关的基因,为系统研究焦虑症的基因网络提供了研究基础。方法从Res Net 11 Mammalian数据库中提取了焦虑症-基因的关系数据,包含592个焦虑症基因。通过基因富集分析、子网络富集分析、网络连通性分析和网络度量分析研究网络属性并选择关键节点。另外,通过采集焦虑症-药物和药物-基因的关系数据,在小分子/药物水平对焦虑症进行病理研究。结果 592中的526个基因富集在100个焦虑症通路(P<1e-15),并显示出较强的基因间相互关联性。综合报导频率,网络中心性和功能多样性的分析,6个基因被推为首选焦虑症基因,包括DRD2、ADORA2A、IL1B、CRH、AVP和CRHR1。此外,538个基因和548个药物强相关,间接支持焦虑症与这些基因之间的关系。结论焦虑症的遗传原因与大量基因构成的遗传网络有关。基因网络以及本研究中提供的文献和量度指标为进一步的生物/遗传学研究奠定了基础。展开更多
Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, l...Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, low odds ratios and penetrance, and a lack of reproducibility have limited their explanatory power. Despite the major efforts made toward identifying environmental factors in schizophrenia, methodological limitations and inconsistent findings of epidemiological reports have obstructed attempts to identify exogenous causal factors. Epigenetic mechanisms, mediating between environment and genes, have recently been proposed to play an important role in the pathogenesis of schizophrenia. DNA methylation is the most stable and well-characterized epigenetic modification. In this paper, we briefly introduce DNA methylation mechanisms, genome-wide DNA methylation studies, and identify specific genomic methylation sites in individuals diagnosed with schizophrenia. The outline candidate genes such as Reelin and COMT, are also outlined before paying attention to the conundrum of recent researches.展开更多
基金supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003 and XDB02030002)the Bureau of Frontier Sciences and Education,Chinese Academy of Sciences (QYZDJ-SSW-SMC005)+3 种基金the National Natural Science Foundation of China (Nos. 81088001,81271484,81471361 and 81371480)the Beijing Training Project for the Leading Talents in S & T (Z151100000315020)the National Key Basic Research and Development Program (973) (2012CB517904)the CAS/SAFEA International Partnership Programme for Creative Research Teams (Y2CX131003)
文摘Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.
文摘背景近年来,众多研究报导了数百种与焦虑症有关的基因,为系统研究焦虑症的基因网络提供了研究基础。方法从Res Net 11 Mammalian数据库中提取了焦虑症-基因的关系数据,包含592个焦虑症基因。通过基因富集分析、子网络富集分析、网络连通性分析和网络度量分析研究网络属性并选择关键节点。另外,通过采集焦虑症-药物和药物-基因的关系数据,在小分子/药物水平对焦虑症进行病理研究。结果 592中的526个基因富集在100个焦虑症通路(P<1e-15),并显示出较强的基因间相互关联性。综合报导频率,网络中心性和功能多样性的分析,6个基因被推为首选焦虑症基因,包括DRD2、ADORA2A、IL1B、CRH、AVP和CRHR1。此外,538个基因和548个药物强相关,间接支持焦虑症与这些基因之间的关系。结论焦虑症的遗传原因与大量基因构成的遗传网络有关。基因网络以及本研究中提供的文献和量度指标为进一步的生物/遗传学研究奠定了基础。
基金supported by the National Natural Science Foundation of China(81271484 and 81471361 toX.C,30900486 and 81371480 to J.T)the National Key Basic Research and Development Program(2012CB517904 to X.C)
文摘Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, low odds ratios and penetrance, and a lack of reproducibility have limited their explanatory power. Despite the major efforts made toward identifying environmental factors in schizophrenia, methodological limitations and inconsistent findings of epidemiological reports have obstructed attempts to identify exogenous causal factors. Epigenetic mechanisms, mediating between environment and genes, have recently been proposed to play an important role in the pathogenesis of schizophrenia. DNA methylation is the most stable and well-characterized epigenetic modification. In this paper, we briefly introduce DNA methylation mechanisms, genome-wide DNA methylation studies, and identify specific genomic methylation sites in individuals diagnosed with schizophrenia. The outline candidate genes such as Reelin and COMT, are also outlined before paying attention to the conundrum of recent researches.
