Haglund, Alexander;
Zuber, Verena;
Abouzeid, Maya;
Yang, Yifei;
Ko, Jeong Hun;
Wiemann, Liv;
Otero-Jimenez, Maria;
... Johnson, Michael R; + view all
(2025)
Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes.
Nature Genetics
10.1038/s41588-024-02050-9.
(In press).
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Abstract
Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case and control brains, we report 13,939 genes whose expression correlated with genetic variation, of which 16.7-40.8% (depending on cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a disease dependency, even after adjusting for disease status. To estimate the unconfounded effect of genes on outcomes, we repeated the analysis using nondiseased brains (n = 183) and reported an additional 91 colocalizations not present in the larger mixed disease and control dataset, demonstrating enhanced interpretation of disease-associated variants. Principled implementation of single-cell Mendelian randomization in control-only brains identified 140 putatively causal gene-trait associations, of which 11 were replicated in the UK Biobank, prioritizing candidate peripheral biomarkers predictive of CNS outcomes.
| Type: | Article |
|---|---|
| Title: | Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41588-024-02050-9 |
| Publisher version: | https://doi.org/10.1038/s41588-024-02050-9 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Genetic association study, Genetics research, Neurological disorders, Transcriptomics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203547 |
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