A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex.
A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex.
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创伤性脑损伤后认知恢复的多巴胺通路基因风险评分：方法学考虑、初步发现以及与性的相互作用。
DOI：
10.1097/htr.0000000000000199
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Wagner,AmyK
中科院分区：
文献类型：
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作者：
Myrga,JohnM;Failla,MichelleD;Ricker,JosephH;Dixon,CEdward;Conley,YvetteP;Arenth,PatriciaM;Wagner,AmyK
ObjectiveObjectives：有证据表明多巴胺（DA）通路的性别二态性，以及DA通路在创伤性脑损伤（TBI）恢复中的重要性，我们假设性别× DA-基因相互作用可能影响TBI-post-TBI的认知。参与者：从1级创伤中心连续招募的严重TBI的成年幸存者（n= 193）。设计：使用性别特异性分层方法对多个DA通路基因进行风险等位基因分配。采用未加权、半加权和加权基因风险评分（GRS）方法，在伤后6个月和12个月评估了遗传风险等位基因及其对认知的影响。002，12M：P=. 001)和COMT rs 4680（6 M：P=. 048; 12M：P=. 004）; DRD2 rs6279（P=. 001)VMAT rs363226（P=. 043)在6个月时，基因型与认知独立相关，在12个月时具有性别×基因相互作用的趋势。在多变量模型中，所有GRS方法都是认知表现的显著预测因子。加权GRS多变量模型捕获的认知最大的方差：R 2= 0.344（6个月），R 2= 0.441（12个月），显着增加从基础预测models.Conclusions捕获的方差：性别特异性DA通路GRS可能是一个有价值的工具时，预测TBI后认知恢复。未来的工作应该验证这些发现，并探讨DA通路遗传学如何指导治疗干预。
Objectives:With evidence of sexual dimorphism involving the dopamine (DA)-pathway, and the importance of DA pathways in traumatic brain injury (TBI) recovery, we hypothesized that sex× DA-gene interactions may influence cognition post-TBI.Participants:Adult survivors of severe TBI (n= 193) consecutively recruited from a level 1 trauma center.Design:Risk allele assignments were made for multiple DA pathway genes using a sex-specific stratified approach. Genetic risk alleles, and their impacts on cognition, were assessed at 6 and 12 months postinjury using unweighted, semiweighted, and weighted gene risk score (GRS) approaches.Main Measures:A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains.Results:A significant sex× gene interaction was observed at 6 and 12 months for ANKK1 rs1800497 (6M: P=. 002, 12M: P=. 001) and COMT rs4680 (6M: P=. 048; 12M: P=. 004); DRD2 rs6279 (P=. 001) and VMAT rs363226 (P=. 043) genotypes were independently associated with cognition at 6 months, with trends for a sex× gene interaction at 12 months. All GRS methods were significant predictors of cognitive performance in multivariable models. Weighted GRS multivariate models captured the greatest variance in cognition: R 2= 0.344 (6 months); R 2= 0.441 (12 months), significantly increasing the variance captured from the base prediction models.Conclusions:A sex-specific DA-pathway GRS may be a valuable tool when predicting cognitive recovery post-TBI. Future work should validate these findings and explore how DA-pathway genetics may guide therapeutic intervention.