| Title: | Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes |
| Journal: | Nature Genetics |
| Published: | 10 Jan 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39794547/ |
| DOI: | https://doi.org/10.1038/s41588-024-02050-9 |
Publication 14884
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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.</p>
13 Keywords
- Alleles
- Brain
- Brain Diseases
- Case-Control Studies
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Humans
- Mendelian Randomization Analysis
- Phenotype
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- Single-Cell Analysis
35 Authors
- Alexander Haglund
- Verena Zuber
- Maya Abouzeid
- Yifei Yang
- Jeong Hun Ko
- Liv Wiemann
- Maria Otero-Jimenez
- Louwai Muhammed
- Rahel Feleke
- Alexi Nott
- James D. Mills
- Liisi Laaniste
- Djordje O. Gveric
- Daniel Clode
- Ann C. Babtie
- Susanna Pagni
- Ravishankara Bellampalli
- Alyma Somani
- Karina McDade
- Jasper J. Anink
- Lucia Mesarosova
- Nurun Fancy
- Nanet Willumsen
- Amy Smith
- Johanna Jackson
- Javier Alegre-Abarrategui
- Eleonora Aronica
- Paul M. Matthews
- Maria Thom
- Sanjay M. Sisodiya
- Prashant K. Srivastava
- Dheeraj Malhotra
- Julien Bryois
- Leonardo Bottolo
- Michael R. Johnson
Enabling scientific discoveries that improve human health