Mapping genetic effects on splicing in ten thousand post-mortem brain samples reveals novel mediators of neurological disease risk

Alternative splicing shapes isoform diversity and gene dosage in the brain, yet its disease impact remains unclear. We assembled BigBrain, an ancestry-aware resource of 10,725 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. To preserve linkage disequilibrium with GWAS, fine-mapping and colocalization were confined to 3,877 Europeans; SuSiE, a Bayesian fine-mapper, resolved over half 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 implicating splicing-mediated genetic risk (57 Schizophrenia, 18 Parkinson’s). Among sQTL-eQTL pairs with PP.H4 ≥ 0.8 (posterior probability of a shared causal variant), 50.1% shared credible-set variants, showing that splicing can complement or act independently of expression. Mechanistic examples include CAMLG, ZDHHC2, and CLU. Preprint: https://www.medrxiv.org/content/10.1101/2025.09.25.25336663v1