Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, China.
MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, China.
Mol Psychiatry. 2022 Jun;27(6):2720-2730. doi: 10.1038/s41380-022-01529-3. Epub 2022 Apr 4.
Neurological and psychiatric disorders have overlapped phenotypic profiles, but the underlying tissue-specific functional processes remain largely unknown. In this study, we explore the shared tissue-specificity among 14 neuropsychiatric disorders through the disrupted long-range gene regulations by GWAS-identified regulatory SNPs. Through Hi-C interactions, averagely 38.0% and 17.2% of the intergenic regulatory SNPs can be linked to target protein-coding genes in brain and non-brain tissues, respectively. Interestingly, while the regulatory target genes in the brain tend to enrich in nervous system development related processes, those in the non-brain tissues are inclined to interfere with synapse and neuroinflammation related processes. Compared to psychiatric disorders, neurological disorders present more prominently the neuroinflammatory processes in both brain and non-brain tissues, indicating an intrinsic difference in mechanisms. Through tissue-specific gene regulatory networks, we then constructed disorder similarity networks in two brain and three non-brain tissues, highlighting both known disorder clusters (e.g. the neurodevelopmental disorders) and unexpected disorder clusters (e.g. Parkinson's disease is consistently grouped with psychiatric disorders). We showcase the potential pharmaceutical applications of the small bowel and its disorder clusters, illustrated by the known drug targets NR1I3 and NFACT1, and their small bowel-specific regulatory modules. In conclusion, disrupted long-range gene regulations in both brain and non-brain tissues contribute to the similarity among distinct clusters of neuropsychiatric disorders, and the tissue-specifically shared functions and regulators for disease clusters may provide insights for future therapeutic investigations.
神经和精神疾病具有重叠的表型特征，但潜在的组织特异性功能过程在很大程度上仍然未知。在这项研究中，我们通过 GWAS 鉴定的调控 SNPs 破坏的长程基因调控，探索了 14 种神经精神疾病之间的共同组织特异性。通过 Hi-C 相互作用，平均 38.0%和 17.2%的基因间调控 SNPs 可以分别与大脑和非大脑组织中的靶蛋白编码基因相关联。有趣的是，虽然大脑中的调控靶基因倾向于富集在神经系统发育相关过程中，但非大脑组织中的调控靶基因则倾向于干扰突触和神经炎症相关过程。与精神疾病相比，神经系统疾病在大脑和非大脑组织中都更突出地表现出神经炎症过程，表明其机制存在内在差异。通过组织特异性基因调控网络，我们构建了两个大脑和三个非大脑组织中的疾病相似性网络，突出了已知的疾病集群（如神经发育障碍）和意想不到的疾病集群（如帕金森病与精神疾病一致分组）。我们展示了小肠及其疾病集群的潜在药物应用，以已知的药物靶点 NR1I3 和 NFACT1 及其小肠特异性调控模块为例。总之，大脑和非大脑组织中长程基因调控的破坏导致了神经精神疾病不同集群之间的相似性，疾病集群的组织特异性共享功能和调控因子可能为未来的治疗研究提供新的见解。
