美国普林斯顿大学Olga G. Troyanskaya、Christopher Y. Park等研究人员合作，通过RNA结合蛋白靶位点失调的全基因组图谱揭示出对精神疾病风险具有重大影响的因素。相关论文于2021年1月18日在线发表在《自然—遗传学》杂志上。

研究人员表示，尽管精神疾病有很强的遗传基础，但潜在的分子机制在很大程度上尚未确定。RNA结合蛋白（RBP）负责大多数转录后调控，从剪接、翻译到定位。因此，RBP充当了细胞动态平衡（尤其是在大脑中）的关键看守者。然而，量化影响RBP靶标位点的非编码变体的致病贡献是具有挑战性的。

研究人员利用深度学习方法来准确预测了突变的RBP靶标位点失调作用，并发现RBP失调是导致精神病风险的主要因素。RBP失调解释了大规模的分子定量性状基因座研究未捕获的大量遗传力，并且比常见的编码区变体具有更强的影响。研究人员共享了RBP失调的全基因组图谱，并用其鉴定出DDHD2是精神分裂症风险候选基因。该资源提供了一个新的分析框架，可将各种RNA调控与复杂疾病联系起来。

附：英文原文

Title: Genome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk

Author: Christopher Y. Park, Jian Zhou, Aaron K. Wong, Kathleen M. Chen, Chandra L. Theesfeld, Robert B. Darnell, Olga G. Troyanskaya

Issue&Volume: 2021-01-18

Abstract: Despite the strong genetic basis of psychiatric disorders, the underlying molecular mechanisms are largely unmapped. RNA-binding proteins (RBPs) are responsible for most post-transcriptional regulation, from splicing to translation to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. However, quantifying the pathogenic contribution of noncoding variants impacting RBP target sites is challenging. Here, we leverage a deep learning approach that can accurately predict the RBP target site dysregulation effects of mutations and discover that RBP dysregulation is a principal contributor to psychiatric disorder risk. RBP dysregulation explains a substantial amount of heritability not captured by large-scale molecular quantitative trait loci studies and has a stronger impact than common coding region variants. We share the genome-wide profiles of RBP dysregulation, which we use to identify DDHD2 as a candidate schizophrenia risk gene. This resource provides a new analytical framework to connect the full range of RNA regulation to complex disease. Genome-wide analysis of RNA-binding protein (RBP) target sites identifies a major role for RBP dysregulation in complex psychiatric disorders and implicates DDHD2 as a candidate risk gene for schizophrenia.

DOI: 10.1038/s41588-020-00761-3

Source: https://www.nature.com/articles/s41588-020-00761-3