Liao Calwing, Moyses-Oliveira Mariana, De Esch Celine E F, Bhavsar Riya, Nuttle Xander, Li Aiqun, Yu Alex, Burt Nicholas D, Erdin Serkan, Fu Jack M, Wang Minghui, Morley Theodore, Han Lide, Dion Patrick A, Rouleau Guy A, Zhang Bin, Brennand Kristen J, Talkowski Michael E, Ruderfer Douglas M
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.
Cell Genom. 2023 Mar 9;3(4):100277. doi: 10.1016/j.xgen.2023.100277. eCollection 2023 Apr 12.
Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein-altering variants in many genes have been shown to contribute to ASD; however, understanding the convergence across many genes remains a challenge. We demonstrate that coexpression patterns from 993 human postmortem brains are significantly correlated with the transcriptional consequences of CRISPR perturbations in human neurons. Across 71 ASD risk genes, there was significant tissue-specific convergence implicating synaptic pathways. Tissue-specific convergence was further demonstrated across schizophrenia and atrial fibrillation risk genes. The degree of ASD convergence was significantly correlated with ASD association from rare variation and differential expression in ASD brains. Positively convergent genes showed intolerance to functional mutations and had shorter coding lengths than known risk genes even after removing association with ASD. These results indicate that convergent coexpression can identify potentially novel genes that are unlikely to be discovered by sequencing studies.
自闭症谱系障碍（ASD）是一种遗传性神经发育障碍，其特征是社交互动和沟通存在缺陷。许多基因中的蛋白质改变变体已被证明与ASD有关；然而，了解众多基因之间的趋同现象仍然是一项挑战。我们证明，来自993个人类死后大脑的共表达模式与人类神经元中CRISPR干扰的转录结果显著相关。在71个ASD风险基因中，存在涉及突触途径的显著组织特异性趋同现象。在精神分裂症和心房颤动风险基因中也进一步证明了组织特异性趋同。ASD趋同程度与罕见变异和ASD大脑中的差异表达所导致的ASD关联显著相关。正向趋同基因对功能突变不耐受，并且即使在去除与ASD的关联后，其编码长度也比已知风险基因短。这些结果表明，趋同共表达可以识别测序研究不太可能发现的潜在新基因。
