在672个不同的发育中人脑中，研究人员发现了15752个基因，这些基因包含基因、亚型和/或剪接定量性状位点，其中3739个位点映射到细胞环境中。基因表达遗传率在发育过程中下降，这可能反映了细胞异质性的增加和神经元成熟的内在特性。亚型水平的调控，尤其是在后三个月，介导了最大比例的GWAS遗传性。通过共定位，研究人员为五种疾病中约60%的GWAS基因座确定了优先机制，超过了成人大脑的研究结果。最后，研究人员将结果与基因和亚型共表达网络联系起来，揭示了发育和疾病中转录组调控的综合情况。
研究人员表示，包括自闭症谱系障碍和精神分裂症在内的神经精神疾病全基因组关联研究（GWAS）显示，发育中大脑的调控元件具有很强的富集性。然而，在没有统一调控图谱的情况下，确定风险基因和机制的优先次序是一项挑战。
附：英文原文
Title: Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain
Author: Cindy Wen, Michael Margolis, Rujia Dai, Pan Zhang, Pawel F. Przytycki, Daniel D. Vo, Arjun Bhattacharya, Nana Matoba, Miao Tang, Chuan Jiao, Minsoo Kim, Ellen Tsai, Celine Hoh, Nil Aygün, Rebecca L. Walker, Christos Chatzinakos, Declan Clarke, Henry Pratt, PsychENCODE Consortium, Mette A. Peters, Mark Gerstein, Nikolaos P. Daskalakis, Zhiping Weng, Andrew E. Jaffe, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger, Nicholas J. Bray, Nenad Sestan, Daniel H. Geschwind, Kathryn Roeder, Alexander Gusev, Bogdan Pasaniuc, Jason L. Stein, Michael I. Love, Katherine S. Pollard, Chunyu Liu, Michael J. Gandal
Issue&Volume: 2024-05-24
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.
DOI: adh0829
Source: https://www.science.org/doi/10.1126/science.adh0829