Wang Zhongju, Zhu Yongchang, Ye Linyan, Li Qiyang, Guo Bo, Zhao Hao, Bao Xiuqin, Zhuo Qiqi, Yang Tengfei, Li Zhaoqiang, Li Shufen, Hao Bingtao, Zhao Cunyou
Department of Medical Genetics, School of Basic Medical Sciences, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, Southern Medical University, Guangzhou, China.
Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China.
NPJ Schizophr. 2021 May 21;7(1):27. doi: 10.1038/s41537-021-00159-y.
Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) <1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. The Atp5md knockout (KO) in mice was associated with abnormal startle reflex and gait, and ATP5MD knockdown (KD) in human induced pluripotent stem cell-derived neurons disrupted the neural development and mitochondrial respiration and ATP production. Moreover, CNNM2-rs1926032 KO could induce downregulation of ATP5MD expression and disruptions of mitochondrial respiration and ATP production. This study constitutes an important mechanistic component that links schizophrenia-associated CNNM2 regions to disruption in energy adenosine system modulation and neuronal function by long-distance chromatin domain downregulation of ATP5MD. This pathogenic mechanism provides therapeutic implications for schizophrenia.
全基因组关联研究（GWAS）加速了与精神分裂症相关的众多基因变异的发现。然而，大多数风险变异的效应大小较小（优势比（OR）<1.2），这表明仍有待发现更多具有功能的风险变异。在此，我们采用基于区域的基因组注释多标记分析（MAGMA），从精神病基因组学联盟（PGC2）精神分裂症GWAS数据中识别包含具有大OR值变异的额外风险位点，然后采用基于汇总数据的孟德尔随机化（SMR）对精神分裂症易感基因进行优先级排序。排名最高的易感基因ATP5MD，编码一种ATP合酶膜亚基，在精神分裂症中被10q24.32精神分裂症相关位点的CNNM2-rs1926032风险等位基因下调。小鼠中的Atp5md基因敲除（KO）与异常的惊吓反射和步态有关，而在人诱导多能干细胞衍生的神经元中敲低（KD）ATP5MD会破坏神经发育、线粒体呼吸和ATP生成。此外，CNNM2-rs1926032基因敲除可诱导ATP5MD表达下调以及线粒体呼吸和ATP生成的破坏。这项研究构成了一个重要的机制组成部分，通过ATP5MD的长距离染色质结构域下调，将精神分裂症相关的CNNM2区域与能量腺苷系统调节和神经元功能的破坏联系起来。这种致病机制为精神分裂症提供了治疗启示。
