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Multiancestry brain pQTL fine-mapping and integration with genome-wide association studies of 21 neurologic and psychiatric conditions

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Wingo, Aliza P., Liu, Yue, Vattathil, Selina M., Gerasimov, Ekaterina S., Mei, Zhen, Ravindran, Suda Parimala, Liu, Jiaqi, Shantaraman, Ananth +15 more·2025·Nature Genetics
DOI 10.1038/s41588-025-02291-2PMC PMC12425806
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Abstract

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.

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  • Common risk variants are enriched in regulatory regions of genes expressed in developing cortical neurons, particularly those involved in synaptic transmission, ion channel activity, and chromatin remodeling.

    “Recent work integrating genome-wide association study (GWAS) results with transcriptomic and proteomic data suggests that common risk variants are enriched in regulatory regions of genes expressed in developing cortical neurons, particularly those involved in synaptic transmission, ion channel activity, and chromatin remodeling (Wingo et al., 2025).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Wingo et al., 2025

    The Results (Multiancestry pQTL fine-mapping; page unavailable) report enrichment of putative causal brain pQTLs in promoter regions. The Results (Molecular processes, drug targets and drug repurposing; page unavailable) also report synapse-related enrichment among candidate proteins for schizophrenia and anxiety. Neither passage establishes that common risk variants are enriched in regulatory regions of genes expressed in developing cortical neurons, or identifies ion channel activity and chromatin remodeling as enriched processes. (LLM, conf=0.85)

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Authors
Wingo, A. P., Liu, Y., Vattathil, S. M., Gerasimov, E. S., Mei, Z., Ravindran, S. P., Liu, J., Shantaraman, A., Seifar, F., Wang, E., Zhang, B., Reddy, J., Allen, M., Ertekin-Taner, N., De Jager, P. L., Fox, E. J., Duong, D. M., Epstein, M. P., Cutler, D. J., Levey, A. I., Bennett, D. A., Seyfried, N. T., & Wingo, T. S.
Affiliations
  • VA Northern California Health Care System (US)
  • University of California, Davis (US)
  • Emory University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Mayo Clinic in Florida (US)
  • Rush University Medical Center (US)
Corresponding author
  • Wingo, Aliza P.
  • Wingo, Thomas S.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2025-09
Volume
57
Issue
9
Pages
2156-2165
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-025-02291-2
PMC
PMC12425806
OpenAlex
W4414064858
Cited by
21
References
13
Citations by year
2026: 20 · 2025: 1
FWCI
12.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01 AG072120, RF1 AG071170)
  • Alzheimer’s Association Zenith Fellows Award
  • NIH/NIA
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
protein quantitative trait loci, brain proteome, neurologic conditions, psychiatric conditions, Mendelian randomization, brain protein expression, coding variants, African Americans, non-Hispanic whites
MeSH terms
White, Mental Disorders, Black or African American, Brain, Chromosome Mapping, Hispanic or Latino, Humans, Nervous System Diseases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Genome-Wide Association Study, Mendelian Randomization Analysis

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