Allele-specific FKBP5 DNA demethylation: a molecular mediator of gene-childhood trauma interactions. Homo sapiens

While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). Overall design: In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.

尽管“遗传易感性（genetic predisposition）与环境暴露（environmental exposures）相互作用，塑造人类大脑的发育与功能，并最终影响精神疾病患病风险”这一研究范式已受到广泛关注，但对应的分子机制仍未阐明。本研究发现，应激激素系统（stress hormone system）的重要调节因子——FK506结合蛋白5（FK506 binding protein 5, FKBP5）基因中，存在一种可改变转录起始位点（transcription start site）与远端增强子（long-range enhancers）之间染色质相互作用（chromatin interaction）的功能多态性（functional polymorphism）；该多态性通过FKBP5基因功能性糖皮质激素反应元件（glucocorticoid response elements, GREs）上的等位基因特异性（allele-specific）、儿童创伤依赖型（childhood trauma-dependent）DNA去甲基化（DNA demethylation），增加了成年后罹患应激相关精神疾病的风险。该去甲基化过程与应激依赖的基因转录增强相关，继而引发应激激素系统的长期失调，并对免疫细胞及参与应激调控的脑区功能产生全局性影响。本次首次阐明的基因型定向长期环境反应性的分子机制，也将为开发应激相关疾病更有效的治疗策略提供关键支撑。本研究通过基因表达芯片（gene expression arrays）检测，探究了FKBP5 rs1360780基因型-环境交互作用对外周血糖皮质激素受体（glucocorticoid receptor, GR）响应基因的mRNA表达的影响；共纳入129名受试者，其中：受儿童虐待且携带风险等位基因者40例、受儿童虐待且携带保护等位基因者15例、未受儿童虐待且携带风险等位基因者60例、未受儿童虐待且携带保护等位基因者14例。实验整体设计：在全部129名受试者中，共有1627个转录本（transcripts）与血浆皮质醇（plasma cortisol）浓度呈显著相关，提示这些转录本具有GR响应性。在受儿童虐待的受试者中，按FKBP5基因型分层后，上述76个转录本与血浆皮质醇水平的相关性存在显著差异（Fisher z检验≥1.96）。针对这76个转录本，在受儿童虐待的风险等位基因携带者（即FKBP5第7内含子（intron 7）发生去甲基化的受试者）中，其与血浆皮质醇的平均绝对相关系数为R=0.23；而在受儿童虐待且携带保护等位基因（FKBP5第7内含子甲基化水平基本保持稳定）的受试者中，该相关系数为R=0.74。这表明，相较于携带保护等位基因的受试者，暴露于创伤的FKBP5风险等位基因携带者表现出相对的GR抵抗（GR-resistance）。在未暴露于创伤的受试者中，这76个转录本的相关系数未出现基因型依赖性差异，提示早期创伤暴露可能通过表观遗传机制（epigenetic mechanisms），增强了FKBP5基因型对GR敏感性的调控作用。上述研究结果表明，携带FKBP5风险等位基因与早期创伤暴露的共同作用，会改变外周血细胞中多个基因的应激激素依赖性调控模式；这可能会强化已报道的早期创伤与免疫及炎症失调之间的关联，进而进一步加剧应激相关疾病的全身症状。