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A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression

Molecular Psychiatry volume 26, pages 6896–6911 (2021)Cite this article

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Abstract

Genome-wide association studies (GWASs) have revealed that genetic variants at the 22q13.2 risk locus were robustly associated with schizophrenia. However, the causal variants at this risk locus and their roles in schizophrenia remain elusive. Here we identify the risk missense variant rs1801311 (located in the 1st exon of NDUFA6 gene) as likely causal for schizophrenia at 22q13.2 by disrupting binding of YY1, TAF1, and POLR2A. We systematically elucidated the regulatory mechanisms of rs1801311 and validated the regulatory effect of this missense variant. Intriguingly, rs1801311 physically interacted with NAGA (encodes the alpha-N-acetylgalactosaminidase, which is mainly involved in regulating metabolisms of glycoproteins and glycolipids in lysosome) and showed the most significant association with NAGA expression in the human brain, with the risk allele (G) associated with higher NAGA expression. Consistent with eQTL analysis, expression analysis showed that NAGA was significantly upregulated in brains of schizophrenia cases compared with controls, further supporting that rs1801311 may confer schizophrenia risk by regulating NAGA expression. Of note, we found that NAGA regulates important neurodevelopmental processes, including proliferation and differentiation of neural stem cells. Transcriptome analysis corroborated that NAGA regulates pathways associated with neuronal differentiation. Finally, we independently confirmed the association between rs1801311 and schizophrenia in a large Chinese cohort. Our study elucidates the regulatory mechanisms of the missense schizophrenia risk variant rs1801311 and provides mechanistic links between risk variant and schizophrenia etiology. In addition, this study also revealed the novel role of coding variants in gene regulation and schizophrenia risk, i.e., genetic variant in coding region of a specific gene may confer disease risk through regulating distal genes (act as regulatory variant for distal genes).

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Fig. 1: Reporter gene assays and EMSA validated the regulatory effect of rs1801311.
Fig. 2: rs1801311 showed the most significant association with NAGA expression in human brain.
Fig. 3: YY1 regulates NAGA expression.
Fig. 4: Naga affects proliferation of NSCs.
Fig. 5: Naga affects differentiation of NSCs.
Fig. 6: Naga regulates schizophrenia-associated pathways.
Fig. 7: The working model of rs1801311 in schizophrenia pathogenesis.

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Acknowledgements

This study was equally supported by the Distinguished Young Scientists grant of the Yunnan Province (202001AV070006) and Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004) to XJL. Also was supported by the National Nature Science Foundation of China (31970561 to XJL, U1904130 to WQL). One of the brain eQTL datasets used in this study were generated as part of the Common Mind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd, and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, and R37MH057881S1, HHSN271201300031C, AG02219, AG05138, and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the NIMH Human Brain Collection Core. CMC Leadership: Pamela Sklar, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, HiroyoshiToyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici, Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite, Mette Peters (Sage Bionetworks), Thomas Lehner, Barbara Lipska (NIMH). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. We thank Miss. Qian Li for her technical assistance.

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Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Yifan Li, Changguo Ma, Xiaoyan Li, Jiewei Liu, Junyang Wang, Shiwu Li, Yixing Liu, Kaiqin Li, Jiao Li, Di Huang, Rui Chen, Ming Li & Xiong-Jian Luo

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Yifan Li, Changguo Ma, Xiaoyan Li, Junyang Wang, Shiwu Li, Yixing Liu, Kaiqin Li, Jiao Li, Rui Chen & Xiong-Jian Luo

  3. Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China

    Wenqiang Li, Yongfeng Yang & Luxian Lv

  4. Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China

    Wenqiang Li, Yongfeng Yang & Luxian Lv

  5. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China

    Xiong-Jian Luo

  6. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Xiong-Jian Luo

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  1. Yifan Li
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Contributions

XJL conceived, designed, and supervised the study. YFL, CGM, JYW, KQL, JL, DH, RC, SWL, and YXL extracted the DNA. YFL performed genotyping assays, reporter gene assays, ChIP-qPCR, knockdown assay, and genome editing. XYL and JWL performed the data analysis. JYW conducted EMSA. YFL and CGM performed proliferation and differentiation of mNSCs assays. YFL wrote the first draft of the manuscript. ML provided critical comments on study design, data interpretation, and manuscript writing. XJL oversaw the project and finalized the manuscript. All authors revised the manuscript critically and approved the final version.

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Correspondence to Xiong-Jian Luo.

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Li, Y., Ma, C., Li, W. et al. A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression. Mol Psychiatry 26, 6896–6911 (2021). https://doi.org/10.1038/s41380-021-01125-x

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