Myrga John M, Failla Michelle D, Ricker Joseph H, Dixon C Edward, Conley Yvette P, Arenth Patricia M, Wagner Amy K
Department of Physical Medicine & Rehabilitation (Mr Myrga and Drs Failla, Dixon, Arenth, and Wagner), Center for Neuroscience (Drs Failla, Dixon, and Wagner), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania; Department of Rehabilitation Medicine, New York University, School of Medicine, New York (Dr Ricker); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania (Dr Dixon); Department of Human Genetics, University of Pittsburgh, School of Public Health, Pittsburgh, Pennsylvania (Dr Conley); Health Promotion & Development, University of Pittsburgh, School of Nursing, Pittsburgh, Pennsylvania (Dr Conley); and Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Dixon, Conley, and Wagner).
J Head Trauma Rehabil. 2016 Sep-Oct;31(5):E15-29. doi: 10.1097/HTR.0000000000000199.
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.
Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center.
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.
A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains.
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 = 0.344 (6 months); R = 0.441 (12 months), significantly increasing the variance captured from the base prediction models.
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.
鉴于有证据表明多巴胺（DA）通路存在性别差异，且DA通路在创伤性脑损伤（TBI）恢复中具有重要性，我们推测性别×DA基因相互作用可能会影响TBI后的认知。
从一级创伤中心连续招募的193名重度TBI成年幸存者。
采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赋值。在受伤后6个月和12个月，使用未加权、半加权和加权基因风险评分（GRS）方法评估遗传风险等位基因及其对认知的影响。
由针对多个认知领域的8项标准化神经心理学测试生成的认知综合评分。
在6个月和12个月时，观察到ANKK1 rs1800497（6个月：P = 0.002，12个月：P = 0.001）和COMT rs4680（6个月：P = 0.048；12个月：P = 0.004）存在显著的性别×基因相互作用；DRD2 rs6279（P = 0.001）和VMAT rs363226（P = 0.043）基因型在6个月时与认知独立相关，在12个月时有性别×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多变量模型在认知方面捕获的方差最大：R = 0.344（6个月）；R = 0.441（12个月），显著增加了从基础预测模型中捕获的方差。
性别特异性DA通路GRS在预测TBI后的认知恢复时可能是一种有价值的工具。未来的工作应验证这些发现，并探索DA通路遗传学如何指导治疗干预。
