Garrett Lillian, Trümbach Dietrich, Lee Donghyung, Mandillo Silvia, Samaco Rodney, Flenniken Ann M, Stewart Michelle, White Jacqueline K, McKerlie Colin, Nutter Lauryl M J, Vukobradovic Igor, Veeraragavan Surabi, Yuva Lisa, Heaney Jason D, Dickinson Mary E, Meziane Hamid, Hérault Yann, Wells Sara, Lloyd K C Kent, Bower Lynette, Lanoue Louise, Clary Dave, Zimprich Annemarie, Gailus-Durner Valerie, Fuchs Helmut, Brown Steve D M, Chesler Elissa J, Wurst Wolfgang, Hrabě de Angelis Martin, Hölter Sabine M
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Neurosci Appl. 2024 Jun 7;3:104075. doi: 10.1016/j.nsa.2024.104075. eCollection 2024.
Schizophrenia is a complex psychiatric disorder with genetic and phenotypic heterogeneity. Accumulating rare and genome-wide association study (GWAS) common risk variant information has yet to yield robust mechanistic insight. Leveraging large-scale gene deletion mouse phenomic data thus has potential to functionally interrogate and prioritize human disease genes. To this end, we applied a cross-species network-based approach to parse an extensive mouse gene set (188 genes) associated with disrupted prepulse inhibition (PPI), a Schizophrenia endophenotype. Integrating PPI genes with high-resolution mouse and human brain transcriptomic data, we identified functional and disease coherent co-expression modules through hierarchical clustering and weighted gene co-expression network analysis (WGCNA). In two modules, Schizophrenia risk and mouse PPI genes converged based on telencephalic patterning. The associated neuronal genes were highly expressed in cingulate cortex and hippocampus; implicated in synaptic function and neurotransmission and overlapped with the greatest proportion of rare variants. Concordant neuroanatomical patterning revealed novel core Schizophrenia-relevant genes consistent with the Omnigenic hypothesis of complex traits. Among other genes discussed, the developmental and post-synaptic scaffold (Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2) emerged from both networks as a novel core genetic driver of Schizophrenia altering PPI. Aspects of psychiatric disease comorbidity and phenotypic heterogeneity are also explored. Overall, this study provides a framework and galvanizes the value of mouse preclinical genetics and PPI to prioritize both existing and novel human Schizophrenia candidate genes as druggable targets.
精神分裂症是一种具有遗传和表型异质性的复杂精神障碍。积累罕见和全基因组关联研究（GWAS）的常见风险变异信息尚未产生强有力的机制性见解。因此，利用大规模基因敲除小鼠表型组数据有可能对人类疾病基因进行功能探究并确定其优先级。为此，我们应用了一种基于跨物种网络的方法来解析与前脉冲抑制（PPI）破坏相关的广泛小鼠基因集（188个基因），PPI是精神分裂症的一种内表型。将PPI基因与高分辨率小鼠和人类大脑转录组数据整合，我们通过层次聚类和加权基因共表达网络分析（WGCNA）确定了功能和疾病相关的共表达模块。在两个模块中，精神分裂症风险基因和小鼠PPI基因基于端脑模式而汇聚。相关的神经元基因在扣带回皮质和海马体中高度表达；与突触功能和神经传递有关，并且与最大比例的罕见变异重叠。一致的神经解剖模式揭示了与复杂性状的全基因假说一致的新型核心精神分裂症相关基因。在讨论的其他基因中，发育和突触后支架蛋白（四肽重复、锚蛋白重复和卷曲螺旋结构域包含蛋白2）从两个网络中脱颖而出，成为改变PPI的精神分裂症新型核心遗传驱动因素。还探讨了精神疾病共病和表型异质性的各个方面。总体而言，本研究提供了一个框架，并凸显了小鼠临床前遗传学和PPI在将现有和新型人类精神分裂症候选基因确定为可药物靶点方面的价值。
