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 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 finemapped 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 (Parkinsons), ZDHHC2 (Schizophrenia), and CLU (Alzheimers).