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可变剪接（Alternative Splicing）塑造了大脑中的转录本多样性与基因剂量，但目前其对疾病的影响仍不明朗。我们构建了BigBrain这一顾及族群背景的资源库，包含来自43个组织-队列组合的4656名个体的10725个RNA测序（RNA-seq）样本及其匹配的基因型数据，并通过混合模型元分析定位了影响10966个基因的68358个顺式剪接数量性状位点（cis-sQTLs）。为保留与全基因组关联研究（Genome-Wide Association Study, GWAS）的连锁不平衡，精细定位与共定位分析仅针对3877名欧洲个体展开；贝叶斯精细定位工具SuSiE将超过半数的信号解析为95%可信集，且常定位至剪接位点附近的单个变异。我们进一步对通过移码突变、无义介导的mRNA降解（Nonsense-Mediated Decay, NMD）改变基因剂量，或破坏蛋白质结构域的预测变异进行了注释。通过与7项神经退行性疾病及精神疾病的GWAS进行共定位分析，我们筛选出97个与剪接介导的遗传风险相关的基因座（其中精神分裂症57个、帕金森病18个）。在后验概率PP.H4≥0.8（即共享因果变异的后验概率）的剪接数量性状位点-表达数量性状位点（sQTL-eQTL）对中，50.1%共享可信集变异，这表明剪接调控可对基因表达调控形成补充，或独立于表达发挥作用。相关机制研究案例包括CAMLG、ZDHHC2及CLU。 预印本：https://www.medrxiv.org/content/10.1101/2025.09.25.25336663v1