Impact of common variants on brain gene expression from RNA to protein to schizophrenia risk
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.
Authors
- Yi Jiang (ORCID: https://orcid.org/0000-0003-0622-0699)
- Junmin Peng (ORCID: https://orcid.org/0000-0003-0472-7648)
- Kevin P. White (ORCID: https://orcid.org/0000-0001-6934-5793)
- Ramu Vadukapuram
- Sidney H. Wang (ORCID: https://orcid.org/0000-0001-8459-1300)
- Mingming Niu
- Bingshan Li (ORCID: https://orcid.org/0000-0003-2129-168X)
- Annie W. Shieh (ORCID: https://orcid.org/0000-0002-1770-5846)
- Kay Grennan
- Lijun Cheng (ORCID: https://orcid.org/0000-0001-7606-9563)
- Gina Giase (ORCID: https://orcid.org/0000-0001-5924-3195)
- Dalila Pinto (ORCID: https://orcid.org/0000-0002-8769-0846)
- Qiuman Liang (ORCID: https://orcid.org/0009-0002-3008-7058)
- Chunyu Liu (ORCID: https://orcid.org/0000-0002-5986-4415)
- Yue Wang (ORCID: https://orcid.org/0000-0002-1788-1102)
- Rui Chen (ORCID: https://orcid.org/0000-0002-4341-2908)
- Chao Chen (ORCID: https://orcid.org/0000-0002-5114-2282)
- Chunling Zhang (ORCID: https://orcid.org/0000-0003-2752-1028)
- Dan Zhou (ORCID: https://orcid.org/0000-0002-5313-8164)
- Xusheng Wang (ORCID: https://orcid.org/0000-0002-1759-9588)
- Feiran Wang
- Meng Xu (ORCID: https://orcid.org/0000-0003-3282-9318)
Institutions
- Northwestern University (US)
- St. Jude Children's Research Hospital (US)
- Allen Institute for Brain Science (US)
- Central South University (CN)
- University of Tennessee Health Science Center (US)
- National University of Singapore (SG)
- Hunan University (CN)
- Vanderbilt University (US)
- SUNY Upstate Medical University (US)
- The University of Texas Rio Grande Valley (US)
- University of Chicago (US)
- Center for Human Genetics (US)
- Child Health and Development Institute (US)
- Brown Foundation (US)
- Second Xiangya Hospital of Central South University (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Huazhong University of Science and Technology (CN)
- Virginia Tech (US)
- The University of Texas Health Science Center at Houston (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-65818-5
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- State University of New York
- National Natural Science Foundation of China
- Central South University
- National Institutes of Health
- State University of New York Upstate Medical University
- National Key Research and Development Program of China