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Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Identifies Novel Risk Genes for Schizophrenia

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Abstract

Multiple integrative studies have been performed to identify the potential target genes of the non-coding schizophrenia (SCZ) risk variants. However, all the integrative studies used expression quantitative trait loci (eQTL) data from bulk tissues. Considering the cell type–specific regulatory effect of many genetic variants, it is important to conduct integrative studies using cell type–specific eQTL data. Here, we conduct a Mendelian randomization (MR) study by integrating genome-wide associations of SCZ (74,776 cases and 101,023 controls) and eQTL data (N = 215) from dopaminergic neurons, which were differentiated from human-induced pluripotent stem cell (iPSC) lines. For eQTL from young post-mitotic dopaminergic neurons (differentiation of iPSC for 30 days, D30), we identified 34 genes whose genetically regulated expression in dopaminergic neurons may have a causal role in SCZ. Among which, ARL3 showed the most significant associations with SCZ. For eQTL from more mature dopaminergic neurons (D52), we identified 37 potential SCZ causal genes, and ARL3 and GNL3 showed the most significant associations. Only 12 genes showed significant associations with SCZ in both D30 and D52 eQTL datasets, indicating the time point–specific genetic regulatory effects in young post-mitotic dopaminergic neurons and more mature dopaminergic neurons. Comparing the results from dopaminergic neurons with bulk brain tissues prioritized 2 high-confidence risk genes, including DDHD2 and GALNT10. Our study identifies multiple risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in SCZ. Further mechanistic investigation will provide pivotal insights into SCZ pathophysiology.

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Acknowledgements

We thank miss Qian Li for her technical assistance.

Funding

This study was equally supported by the National Nature Science Foundation of China (U2102205 and 31970561 to XJL, 81830040 and 82130042 to ZJZ) and the Distinguished Young Scientists grant of the Yunnan Province (202001AV070006). This study was also supported by the Key Research Project of Yunnan Province (202101AS070055 to XJL), the Science and Technology of Guangdong province (2018B030334001 to ZJZ), the CAS “Light of West China” Program to JWL, and Yunnan Fundamental Research Projects (202001AT070099) to JWL.

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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, 650223, Yunnan, China

    Xinglun Dang & Jiewei Liu

  2. Zhongda Hospital, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China

    Zhijun Zhang & Xiong-Jian Luo

  3. Department of Neurology, School of Medicine, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, Southeast University, Nanjing, 210009, Jiangsu Province, China

    Zhijun Zhang & Xiong-Jian Luo

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  1. Xinglun Dang
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  2. Jiewei Liu
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Contributions

XJL conceived, designed, and supervised the whole study. XLD performed most of the analyses. JWL conducted the PPI analysis. XLD, JWL, XJL, and ZJZ interpreted the results. XJL and ZJZ wrote the manuscript. All authors provided critical comments and approved the final manuscript.

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Correspondence to Xiong-Jian Luo.

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Dang, X., Liu, J., Zhang, Z. et al. Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Identifies Novel Risk Genes for Schizophrenia. Mol Neurobiol 60, 1537–1546 (2023). https://doi.org/10.1007/s12035-022-03160-3

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