Wen Cindy, Margolis Michael, Dai Rujia, Zhang Pan, Przytycki Pawel F, Vo Daniel D, Bhattacharya Arjun, Matoba Nana, Jiao Chuan, Kim Minsoo, Tsai Ellen, Hoh Celine, Aygün Nil, Walker Rebecca L, Chatzinakos Christos, Clarke Declan, Pratt Henry, Consortium PsychENCODE, Peters Mette A, Gerstein Mark, Daskalakis Nikolaos P, Weng Zhiping, Jaffe Andrew E, Kleinman Joel E, Hyde Thomas M, Weinberger Daniel R, Bray Nicholas J, Sestan Nenad, Geschwind Daniel H, Roeder Kathryn, Gusev Alexander, Pasaniuc Bogdan, Stein Jason L, Love Michael I, Pollard Katherine S, Liu Chunyu, Gandal Michael J
Interdepartmental Program in Bioinformatics, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
medRxiv. 2023 Mar 6:2023.03.03.23286706. doi: 10.1101/2023.03.03.23286706.
Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations. We identify 15,752 genes harboring a significant xQTL and map 3,739 eQTLs to a specific cellular context. We observe a striking drop in gene expression and splicing heritability as the human brain develops. Isoform-level regulation, particularly in the second trimester, mediates the greatest proportion of heritability across multiple psychiatric GWAS, compared with eQTLs. Via colocalization and TWAS, we prioritize biological mechanisms for ~60% of GWAS loci across five neuropsychiatric disorders, nearly two-fold that observed in the adult brain. Finally, we build a comprehensive set of developmentally regulated gene and isoform co-expression networks capturing unique genetic enrichments across disorders. Together, this work provides a comprehensive view of genetic regulation across human brain development as well as the stage-and cell type-informed mechanistic underpinnings of neuropsychiatric disorders.
在发育中的人类大脑中活跃的基因组调控元件在神经精神疾病的遗传风险中显著富集，这些疾病包括自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍。然而，由于缺乏一个统一的大规模人类大脑发育基因调控图谱，确定这些遗传富集背后的特定风险基因和候选分子机制受到了阻碍。在这里，我们对来自多个祖先群体的独特个体的672份胎儿脑样本中的基因、异构体和剪接定量性状位点（xQTL）进行了统一处理和系统表征。我们鉴定出15752个含有显著xQTL的基因，并将3739个eQTL定位到特定的细胞背景中。我们观察到随着人类大脑的发育，基因表达和剪接遗传力显著下降。与eQTL相比，异构体水平的调控，尤其是在妊娠中期，在多个精神疾病全基因组关联研究（GWAS）中介导了最大比例的遗传力。通过共定位和转录组全基因关联研究（TWAS），我们确定了五种神经精神疾病中约60%的GWAS位点的生物学机制，这一比例几乎是在成人大脑中观察到的两倍。最后，我们构建了一组全面的发育调控基因和异构体共表达网络，捕捉了不同疾病中独特的遗传富集。总之，这项工作提供了人类大脑发育过程中遗传调控的全面视图，以及神经精神疾病的阶段和细胞类型相关的机制基础。
