阐明与中重度儿科创伤后行为和执行功能相关的基因组特征:一种系统生物学方法

B. Kurowski, A. Treble-Barna, Valentina Pilipenko, Lisa J. Martin, Anil G. Jegga, Aimee E Miley, Nanhua Zhang, Anthony Fabio, Ranjit S. Chima, Anna-Lynne R. Adlam, Kenneth Kaufman, Michael J Bell, Sue R Beers, Stephen R. Wisniewski, Shari L. Wade
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摘要

导言:小儿创伤性脑损伤(TBI)后的行为和执行功能存在很大的变异,原因不明。先前的研究表明,这可能与遗传因素有关;但目前的研究还很有限。本研究的目的是利用系统生物学方法来描述与儿童中度至重度创伤性脑损伤后 12 个月内的行为和执行功能相关的基因组特征:参与者来自两个前瞻性队列,分别是重度创伤性脑损伤儿童组(队列 1)和中度创伤性脑损伤及矫形损伤(OI)儿童组(队列 2)。参与者包括 196 名儿童(每个队列中分别有 72 名和 124 名儿童),受伤时年龄在 0-17 岁之间。其中,86 名儿童患有严重创伤性脑损伤,49 名儿童患有中度创伤性脑损伤,61 名儿童患有开放性损伤。通过儿童行为检查表评估总体行为功能,并在受伤后 12 个月内通过执行功能行为评级量表评估执行功能。为了测试基因组特征,我们比较了系统生物学鉴定基因中与结果相关的名义上有意义(p < 0.05)的多态性数量,以及使用对照基因(如系统生物学未涉及的基因)进行的10,000次排列组合。我们使用 Toppgene Suite 中的 ToppFun 应用程序来识别可能与行为和执行功能结果相关的富集生物过程:结果:在受伤后 12 个月,受伤类型(创伤性脑损伤与脑损伤)与多态性的交互作用在系统生物学选定的行为和执行功能结果基因中显著富集,表明这些基因形成了基因组特征。与我们感兴趣的基因相关的效应大小在前 5%的变异中介于 0.2-.5 之间。对与前 5%效应大小相关的变异进行的系统生物学分析表明,这些变异丰富了几个特定的生物过程和系统:讨论:研究结果表明,基因组特征可以解释中度和重度创伤性脑损伤后行为和执行结果的异质性。这项工作为构建基因组特征以及将系统生物学和遗传信息整合到未来的康复、预后和治疗算法中奠定了基础。
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Elucidating a genomic signature associated with behavioral and executive function after moderate to severe pediatric TBI: a systems biology informed approach
Introduction: There is significant unexplained variability in behavioral and executive functioning after pediatric traumatic brain injury (TBI). Prior research indicates that there are likely genetic contributions; however, current research is limited. The purpose of this study is to use a systems biology informed approach to characterize the genomic signature related to behavioral and executive functioning ∼12 months after moderate through severe TBI in children.Methods: Participants were from two prospective cohorts of children with severe TBI (Cohort #1) and moderate-severe TBI and an orthopedic injury (OI) group (Cohort #2). Participants included 196 children (n = 72 and n = 124 total from each respective cohort), ranging in age between 0–17 years at the time of injury. In total, 86 children had severe TBI, 49 had moderate TBI, and 61 had an OI. Global behavioral functioning assessed via the Child Behavior Checklist and executive function assessed via the Behavioral Rating Inventory of Executive Function at ∼ 12 months post injury served as outcomes. To test for a genomic signature, we compared the number of nominally significant (p < 0.05) polymorphisms associated with the outcomes in our systems biology identified genes to a set 10,000 permutations using control genes (e.g., not implicated by systems biology). We used the ToppFun application from Toppgene Suite to identify enriched biologic processes likely to be associated with behavioral and executive function outcomes.Results: At 12 months post injury, injury type (TBI vs OI) by polymorphism interaction was significantly enriched in systems biology selected genes for behavioral and executive function outcomes, suggesting these genes form a genomic signature. Effect sizes of the associations from our genes of interest ranged from .2–.5 for the top 5% of variants. Systems biology analysis of the variants associated with the top 5% effect sizes indicated enrichment in several specific biologic processes and systems.Discussion: Findings indicate that a genomic signature may explain heterogeneity of behavioral and executive outcomes after moderate and severe TBI. This work provides the foundation for constructing genomic signatures and integrating systems biology and genetic information into future recovery, prognostic, and treatment algorithms.
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