Scholarlink

<p>Genome-wide association studies have identified 1p36.23 as a schizophrenia risk locus. However, the functional variants and genes driving the association remain unknown. Here, we identified two functional variants (i.e., rs159961 and rs301792) at the 1p36.23 risk locus. Both variants reside introns of <i>RERE</i> and exhibit allele-specific enhancer activity. Risk alleles of rs159961 and rs301792 increase enhancer activity by altering REST and POLR2A binding, leading to <i>RERE</i> upregulation. Consistently, <i>RERE</i> was significantly elevated in brains of schizophrenia cases. Functionally, <i>RERE</i>-overexpression impaired neurogenesis, altered dendritic spine density and dendritic complexity, and altered genes related to dendrite development and glutamatergic synapses. Through interacting with RARB and RXRA at the <i>Grin2a</i> promoter, RERE regulates the well-known schizophrenia risk gene <i>Grin2a</i> (encodes an NMDAR subunit), and <i>RERE</i>-overexpression impairs excitatory synaptic transmission. Our study indicates that functional variants rs159961 and rs301792 confer schizophrenia risk by upregulating <i>RERE</i>, which affects neuronal development and synaptic function.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Functional variants at 1p36.23 confer risk of schizophrenia through modulating RERE

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月24日

查看全文
  • Yixing Liu,
  • Junyang Wang,
  • Hong Yang,
  • Yifan Li,
  • Changgai Mu,
  • Xinglun Dang,
  • Xinran Chen,
  • Danyang Li,
  • Mingna Li,
  • Jiewei Liu,
  • Shiwu Li,
  • Jinfeng Yang,
  • Xi Chen,
  • Chen Zhang,
  • Jin Feng,
  • Xiong-Jian Luo

摘要

Genome-wide association studies have identified 1p36.23 as a schizophrenia risk locus. However, the functional variants and genes driving the association remain unknown. Here, we identified two functional variants (i.e., rs159961 and rs301792) at the 1p36.23 risk locus. Both variants reside introns of RERE and exhibit allele-specific enhancer activity. Risk alleles of rs159961 and rs301792 increase enhancer activity by altering REST and POLR2A binding, leading to RERE upregulation. Consistently, RERE was significantly elevated in brains of schizophrenia cases. Functionally, RERE-overexpression impaired neurogenesis, altered dendritic spine density and dendritic complexity, and altered genes related to dendrite development and glutamatergic synapses. Through interacting with RARB and RXRA at the Grin2a promoter, RERE regulates the well-known schizophrenia risk gene Grin2a (encodes an NMDAR subunit), and RERE-overexpression impairs excitatory synaptic transmission. Our study indicates that functional variants rs159961 and rs301792 confer schizophrenia risk by upregulating RERE, which affects neuronal development and synaptic function.