Jovanovic Tanja, Stenson Anaïs F, Thompson Nadia, Clifford Aimee, Compton Alisha, Minton Sean, van Rooij Sanne J F, Stevens Jennifer S, Lori Adriana, Nugent Nicole, Gillespie Charles F, Bradley Bekh, Ressler Kerry J
Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, USA.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
Neuropsychopharmacology. 2020 Sep;45(10):1603-1608. doi: 10.1038/s41386-020-0748-2. Epub 2020 Jun 26.
Dysregulated fear conditioned responses have been associated with PTSD in adults, with increased fear-potentiated startle (FPS) serving as a potential intermediate phenotype for PTSD risk. This phenotype has also been associated with stress-related ADCYAP1R1 gene variants in adult women. However, FPS and genotype have not yet been examined during development. The aim of this study was to examine developmental changes in fear conditioning, and to see whether these changes were impacted by genotype and trauma. Differential fear conditioning using FPS was tested in n = 63 children ages 8-13 at two visits (V1, V2) 1 year apart. Startle response was measured using electromyograph recordings of the eyeblink muscle. The rs2267735 SNP of the ADCYAP1R1 gene was extracted from genome-wide (GWAS) analyses. Trauma exposure was assessed using the Violence Exposure Scale-Revised (VEX-R). We found significant Visit by Genotype interactions, with CC genotype increasing FPS from V1 to V2. At V2 there was a Genotype by Violence interaction, with higher FPS in the CC vs G allele groups among those with higher violence exposure (F = 17.46, p = 0.0002). Females with the CC genotype had higher FPS compared to G allele females (F = 12.09, p = 0.002); there were no effects of genotype in males. This study showed Gene × Environment × Development and Gene × Sex effects of ADCYAP1R1 in a high-risk pediatric population. Those with the CC genotype and high levels of violence exposure, as well as females with the CC genotype, showed the greatest conditioned fear responses in adolescence.
失调的恐惧条件反应与成年人的创伤后应激障碍（PTSD）有关，恐惧增强惊吓（FPS）增加是PTSD风险的潜在中间表型。这种表型也与成年女性中与应激相关的ADCYAP1R1基因变异有关。然而，在发育过程中尚未对FPS和基因型进行研究。本研究的目的是检查恐惧条件反射的发育变化，并观察这些变化是否受到基因型和创伤的影响。在63名8至13岁的儿童中，相隔1年进行两次访视（V1、V2），使用FPS测试差异恐惧条件反射。使用眨眼肌肉的肌电图记录测量惊吓反应。从全基因组（GWAS）分析中提取ADCYAP1R1基因的rs2267735单核苷酸多态性。使用修订后的暴力暴露量表（VEX-R）评估创伤暴露情况。我们发现了显著的访视与基因型交互作用，CC基因型使FPS从V1增加到V2。在V2时存在基因型与暴力的交互作用，在暴力暴露较高的人群中，CC基因型组的FPS高于G等位基因组（F = 17.46，p = 0.0002）。与G等位基因女性相比，CC基因型女性的FPS更高（F = 12.09，p = 0.002）；男性中不存在基因型效应。本研究显示了ADCYAP1R1在高危儿科人群中的基因×环境×发育和基因×性别效应。具有CC基因型且暴力暴露水平高的人群，以及具有CC基因型的女性，在青春期表现出最大的条件恐惧反应。
