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Impact of common variants on brain gene expression from RNA to protein to schizophrenia risk

Author

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  • Qiuman Liang

    (Central South University, MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital)

  • Yi Jiang

    (Central South University, MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital
    Huazhong University of Science and Technology, Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College)

  • Annie W. Shieh

    (The University of Texas Health Science Center at Houston, Center for Human Genetics, The Brown foundation Institute of Molecular Medicine)

  • Dan Zhou

    (Zhejiang University School of Medicine, School of Public Health and the Second Affiliated Hospital
    Vanderbilt University, Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute)

  • Rui Chen

    (Vanderbilt University, Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute)

  • Feiran Wang

    (Central South University, MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital)

  • Meng Xu

    (Central South University, MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital)

  • Mingming Niu

    (St. Jude Children’s Research Hospital, Department of Structural Biology, Center for Proteomics and Metabolomics
    St. Jude Children’s Research Hospital, Department of Developmental Neurobiology, Center for Proteomics and Metabolomics)

  • Xusheng Wang

    (University of Tennessee Health Science Center, Department of Neurology)

  • Dalila Pinto

    (Icahn School of Medicine at Mount Sinai, Department of Psychiatry, and Seaver Autism Center for Research and Treatment
    Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, and Icahn Genomics Institute
    Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute
    Icahn School of Medicine at Mount Sinai, Friedman Brain Institute)

  • Yue Wang

    (Virginia Polytechnic Institute and State University, Department of Electrical and Computer Engineering)

  • Lijun Cheng

    (University of Chicago, Institute for Genomics and Systems Biology)

  • Ramu Vadukapuram

    (The University of Texas Rio Grande Valley, Department of Psychiatry)

  • Chunling Zhang

    (SUNY Upstate Medical University, Department of Neuroscience and Physiology)

  • Kay Grennan

    (SUNY Upstate Medical University, Department of Psychiatry)

  • Gina Giase

    (Northwestern University, The Feinberg School of Medicine)

  • Kevin P. White

    (National University of Singapore, Department of Biochemistry, Yong Loo Lin School of Medicine)

  • Junmin Peng

    (St. Jude Children’s Research Hospital, Department of Structural Biology, Center for Proteomics and Metabolomics
    St. Jude Children’s Research Hospital, Department of Developmental Neurobiology, Center for Proteomics and Metabolomics)

  • Bingshan Li

    (Vanderbilt University, Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute)

  • Chunyu Liu

    (Central South University, MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital
    SUNY Upstate Medical University, Department of Psychiatry)

  • Chao Chen

    (Central South University, MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital
    Furong Laboratory
    Central South University, Hunan Key Laboratory of Animal Models for Human Diseases)

  • Sidney H. Wang

    (The University of Texas Health Science Center at Houston, Center for Human Genetics, The Brown foundation Institute of Molecular Medicine)

Abstract

Genetic variants influencing gene expression have been extensively studied at the transcriptional level. How these variants affect downstream processes remains unclear. We quantitated ribosome occupancy in prefrontal cortex samples from the BrainGVEX cohort and integrated these data with transcriptomic and proteomic profiles from the same individuals. Through cis-QTL mapping, we identified genetic variants associated with transcript level (eQTLs), ribosome occupancy (rQTLs), and protein level (pQTLs). Notably, only 34% of eQTLs have their effects propagated to the protein levels, suggesting widespread post-transcriptional attenuation. Using both a gene-based approach and a variant-based approach we identified omics-specific QTLs that associated with brain disorder GWAS signals and found the majority of them to be driven predominantly by transcriptional regulation. Consistently, using a TWAS approach, we identified 74 SCZ risk genes across the three omics layers, 52 were discovered using transcriptome with 68% showing limited impact on protein expression. Our findings indicated that many disease-associated variants act through regulatory mechanisms that do not lead to an observable impact on the protein level.

Suggested Citation

  • Qiuman Liang & Yi Jiang & Annie W. Shieh & Dan Zhou & Rui Chen & Feiran Wang & Meng Xu & Mingming Niu & Xusheng Wang & Dalila Pinto & Yue Wang & Lijun Cheng & Ramu Vadukapuram & Chunling Zhang & Kay G, 2025. "Impact of common variants on brain gene expression from RNA to protein to schizophrenia risk," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65818-5
    DOI: 10.1038/s41467-025-65818-5
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