PMID- 34021155
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210604
IS  - 2334-265X (Print)
IS  - 2334-265X (Electronic)
IS  - 2334-265X (Linking)
VI  - 7
IP  - 1
DP  - 2021 May 21
TI  - Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 
      schizophrenia-associated locus involved in impaired ATP production and 
      neurodevelopment.
PG  - 27
LID - 10.1038/s41537-021-00159-y [doi]
LID - 27
AB  - 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.
FAU - Wang, Zhongju
AU  - Wang Z
AD  - 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.
AD  - 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.
FAU - Zhu, Yongchang
AU  - Zhu Y
AD  - Institute of Cancer Research, School of Basic Medical Sciences, Southern Medical 
      University, Guangzhou, Guangdong, China.
FAU - Ye, Linyan
AU  - Ye L
AD  - 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.
FAU - Li, Qiyang
AU  - Li Q
AUID- ORCID: 0000-0003-2214-9968
AD  - 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.
FAU - Guo, Bo
AU  - Guo B
AD  - 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.
FAU - Zhao, Hao
AU  - Zhao H
AD  - Institute of Cancer Research, School of Basic Medical Sciences, Southern Medical 
      University, Guangzhou, Guangdong, China.
FAU - Bao, Xiuqin
AU  - Bao X
AD  - 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.
FAU - Zhuo, Qiqi
AU  - Zhuo Q
AD  - 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.
FAU - Yang, Tengfei
AU  - Yang T
AD  - 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.
AD  - 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.
FAU - Li, Zhaoqiang
AU  - Li Z
AD  - Institute of Cancer Research, School of Basic Medical Sciences, Southern Medical 
      University, Guangzhou, Guangdong, China.
FAU - Li, Shufen
AU  - Li S
AD  - 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.
AD  - 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.
FAU - Hao, Bingtao
AU  - Hao B
AD  - Institute of Cancer Research, School of Basic Medical Sciences, Southern Medical 
      University, Guangzhou, Guangdong, China. haobt123@smu.edu.cn.
FAU - Zhao, Cunyou
AU  - Zhao C
AUID- ORCID: 0000-0001-6116-4584
AD  - 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. 
      cyzhao@smu.edu.cn.
LA  - eng
GR  - 2019B030316032/Guangdong Science and Technology Department (Science and 
      Technology Department, Guangdong Province)/
GR  - 81671333, 81871049/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 2020M682806/China Postdoctoral Science Foundation/
PT  - Journal Article
DEP - 20210521
PL  - United States
TA  - NPJ Schizophr
JT  - NPJ schizophrenia
JID - 101657919
PMC - PMC8139961
COIS- The authors declare no competing interests.
EDAT- 2021/05/23 06:00
MHDA- 2021/05/23 06:01
PMCR- 2021/05/21
CRDT- 2021/05/22 05:44
PHST- 2020/11/03 00:00 [received]
PHST- 2021/04/21 00:00 [accepted]
PHST- 2021/05/22 05:44 [entrez]
PHST- 2021/05/23 06:00 [pubmed]
PHST- 2021/05/23 06:01 [medline]
PHST- 2021/05/21 00:00 [pmc-release]
AID - 10.1038/s41537-021-00159-y [pii]
AID - 159 [pii]
AID - 10.1038/s41537-021-00159-y [doi]
PST - epublish
SO  - NPJ Schizophr. 2021 May 21;7(1):27. doi: 10.1038/s41537-021-00159-y.