Journal article
Aline Réal, Kailash Bp, Winston H. Cuddleston, Benjamin Z Muller, Beomjin Jang, A. Tokolyi, Hong-Hee Won, Jack Humphrey, T. Raj, D. A. Knowles
medRxiv, 2025
medRxiv, 2025
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DOI
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APA
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Réal, A., Bp, K., Cuddleston, W. H., Muller, B. Z., Jang, B., Tokolyi, A., … Knowles, D. A. (2025). Mapping genetic effects on splicing in ten thousand post-mortem brain samples reveals novel mediators of neurological disease risk. MedRxiv.
Chicago/Turabian
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Réal, Aline, Kailash Bp, Winston H. Cuddleston, Benjamin Z Muller, Beomjin Jang, A. Tokolyi, Hong-Hee Won, Jack Humphrey, T. Raj, and D. A. Knowles. “Mapping Genetic Effects on Splicing in Ten Thousand Post-Mortem Brain Samples Reveals Novel Mediators of Neurological Disease Risk.” medRxiv (2025).
MLA
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Réal, Aline, et al. “Mapping Genetic Effects on Splicing in Ten Thousand Post-Mortem Brain Samples Reveals Novel Mediators of Neurological Disease Risk.” MedRxiv, 2025.
BibTeX Click to copy
@article{aline2025a,
title = {Mapping genetic effects on splicing in ten thousand post-mortem brain samples reveals novel mediators of neurological disease risk},
year = {2025},
journal = {medRxiv},
author = {Réal, Aline and Bp, Kailash and Cuddleston, Winston H. and Muller, Benjamin Z and Jang, Beomjin and Tokolyi, A. and Won, Hong-Hee and Humphrey, Jack and Raj, T. and Knowles, D. A.}
}
Abstract
Alternative splicing shapes isoform diversity and gene dosage but how genetic variation impacts splicing in brain disease is still not fully characterized. We assembled BigBrain, a multi-ancestry resource of 10,725 bulk RNA-seq profiles with matched genotypes from 4,656 individuals across 43 tissue-cohort pairs, and mapped 68,358 cis-sQTLs affecting 10,966 genes using mixed-model meta-analysis. Using SuSiE, we were able to finemap over half of these sQTLs into 95% credible sets, frequently to a single variant near splice sites. We further annotated variants predicted to alter dosage through frameshifts or nonsense-mediated decay or disrupt protein domains. Colocalization with seven neurodegenerative and psychiatric GWAS highlighted 97 loci where alternative splicing appears to mediate genetic risk. Among sQTL-eQTL pairs with colocalization probability [≥] 0.8 (posterior probability of a shared causal variant), half shared credible-set variants, showing that splicing can complement or act independently of expression. Mechanistic examples include CAMLG, ZDHHC2, and CLU.