Abstract：
Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.
摘要：
神经精神病学全基因组关联研究(GWAS)，包括自闭症谱系障碍和精神分裂症，在发育中的大脑中显示出对调节元素的强烈富集。然而,如果没有统一的监管图集，优先考虑风险基因和机制是具有挑战性的。在672个不同的发育中的人类大脑中，我们确定了15,752个带有基因的基因，同工型,和/或剪接数量性状基因座，将3739映射到蜂窝上下文。基因表达遗传力在发育过程中下降，可能反映了细胞异质性的增加和神经元成熟的内在特性。等形式级调节，特别是在妊娠中期，介导的GWAS遗传力比例最大。通过共同定位，我们在五种疾病中优先考虑了大约60％的GWAS基因座的机制，超过成人大脑的发现。最后,我们将基因和同工型共表达网络中的结果情境化，揭示了转录组调控在发育和疾病中的综合景观。
