Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment

Abstract 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 e...

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Autores principales:	Zhongju Wang, Yongchang Zhu, Linyan Ye, Qiyang Li, Bo Guo, Hao Zhao, Xiuqin Bao, Qiqi Zhuo, Tengfei Yang, Zhaoqiang Li, Shufen Li, Bingtao Hao, Cunyou Zhao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Psychiatry RC435-571
Acceso en línea:	https://doaj.org/article/c0c06e45dbe54f7f9d03f0db77e8522e
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spelling	oai:doaj.org-article:c0c06e45dbe54f7f9d03f0db77e8522e2021-12-02T15:52:24ZDownregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment10.1038/s41537-021-00159-y2334-265Xhttps://doaj.org/article/c0c06e45dbe54f7f9d03f0db77e8522e2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41537-021-00159-yhttps://doaj.org/toc/2334-265XAbstract 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.Zhongju WangYongchang ZhuLinyan YeQiyang LiBo GuoHao ZhaoXiuqin BaoQiqi ZhuoTengfei YangZhaoqiang LiShufen LiBingtao HaoCunyou ZhaoNature PortfolioarticlePsychiatryRC435-571ENnpj Schizophrenia, Vol 7, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Psychiatry RC435-571
spellingShingle	Psychiatry RC435-571 Zhongju Wang Yongchang Zhu Linyan Ye Qiyang Li Bo Guo Hao Zhao Xiuqin Bao Qiqi Zhuo Tengfei Yang Zhaoqiang Li Shufen Li Bingtao Hao Cunyou Zhao Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
description	Abstract 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.
format	article
author	Zhongju Wang Yongchang Zhu Linyan Ye Qiyang Li Bo Guo Hao Zhao Xiuqin Bao Qiqi Zhuo Tengfei Yang Zhaoqiang Li Shufen Li Bingtao Hao Cunyou Zhao
author_facet	Zhongju Wang Yongchang Zhu Linyan Ye Qiyang Li Bo Guo Hao Zhao Xiuqin Bao Qiqi Zhuo Tengfei Yang Zhaoqiang Li Shufen Li Bingtao Hao Cunyou Zhao
author_sort	Zhongju Wang
title	Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
title_short	Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
title_full	Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
title_fullStr	Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
title_full_unstemmed	Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
title_sort	downregulation by cnnm2 of atp5md expression in the 10q24.32 schizophrenia-associated locus involved in impaired atp production and neurodevelopment
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c0c06e45dbe54f7f9d03f0db77e8522e
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Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment

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