Multiancestry brain pQTL fine-mapping and integration with genome-wide association studies of 21 neurologic and psychiatric conditions
To understand shared and ancestry-specific genetic control of brain protein expression and its ramifications for disease, we mapped protein quantitative trait loci (pQTLs) in 1,362 brain proteomes from African American, Hispanic/Latin American and non-Hispanic white donors. Among the pQTLs that multiancestry fine-mapping MESuSiE confidently assigned as putative causal pQTLs in a specific population, most were shared across the three studied populations and are referred to as multiancestry causal pQTLs. These multiancestry causal pQTLs were enriched for exonic and promoter regions. To investigate their effects on disease, we modeled the 858 multiancestry causal pQTLs as instrumental variables using Mendelian randomization and genome-wide association study results for neurologic and psychiatric conditions (21 traits in participants with European ancestry, 10 in those with African ancestry and 4 in Hispanic participants). We identified 119 multiancestry pQTL-protein pairs consistent with a causal role in these conditions. Remarkably, 29% of the multiancestry pQTLs in these pairs were coding variants. These results lay an important foundation for the creation of new molecular models of neurologic and psychiatric conditions that are likely to be relevant to individuals across different genetic ancestries.
Authors
- Jiaqi Liu (ORCID: https://orcid.org/0000-0003-3480-3234)
- David J. Cutler (ORCID: https://orcid.org/0000-0001-6394-6731)
- Selina Vattathil (ORCID: https://orcid.org/0000-0001-5616-4184)
- Joseph S. Reddy (ORCID: https://orcid.org/0000-0002-1783-4453)
- Nicholas T. Seyfried (ORCID: https://orcid.org/0000-0002-4507-624X)
- Allan I. Levey (ORCID: https://orcid.org/0000-0002-3153-502X)
- Erming Wang (ORCID: https://orcid.org/0009-0000-8056-0785)
- Ekaterina S. Gerasimov (ORCID: https://orcid.org/0000-0002-3986-352X)
- Michael P. Epstein (ORCID: https://orcid.org/0000-0001-9647-9738)
- Philip L. De Jager (ORCID: https://orcid.org/0000-0002-8057-2505)
- Suda Parimala Ravindran (ORCID: https://orcid.org/0000-0002-6745-4977)
- Fatemeh Seifar (ORCID: https://orcid.org/0000-0003-0387-6991)
- Duc Minh Duong (ORCID: https://orcid.org/0000-0001-5880-1888)
- Anantharaman Shantaraman (ORCID: https://orcid.org/0000-0003-1384-941X)
- Nilüfer Ertekin‐Taner (ORCID: https://orcid.org/0000-0003-4436-8889)
- Mariet Allen (ORCID: https://orcid.org/0000-0002-2685-427X)
- Aliza P. Wingo (ORCID: https://orcid.org/0000-0002-6360-6726)
- Yue Liu (ORCID: https://orcid.org/0000-0002-0084-863X)
- Bin Zhang (ORCID: https://orcid.org/0000-0002-9549-5653)
- Edward J. Fox
- Zhen Mei (ORCID: https://orcid.org/0000-0003-0580-8423)
- Thomas S. Wingo (ORCID: https://orcid.org/0000-0002-7679-6282)
Institutions
- Rush University Medical Center (US)
- Emory University (US)
- Columbia University Irving Medical Center (US)
- University of California System (US)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Mayo Clinic in Florida (US)
- VA Northern California Health Care System (US)
- University of California, Davis (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41588-025-02291-2
- Citations
- 5
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 9.09
Funders
- U.S. Department of Veterans Affairs
- Alzheimer's Association
- Emory University
- Arizona Department of Health Services
- Rush University
- Arizona Biomedical Research Commission