Cross-species glucocorticoid-sensitive hippocampal gene network: developing a polygenic score associated with susceptibility to psychiatric conditions in response to adversity in humans

The risk for psychiatric disorders is strongly affected by environmental stressors. The underlying mechanisms are inevitably multifactorial still not fully understood. Glucocorticoids (GCs), which are prominent stress mediators that affect transcriptional activity and brain morphology, are implicated in the pathophysiology of multiple forms of psychopathology. The challenge is that of establishing the relevance of GC-related transcriptional effects for stress-related psychopathology in humans. We addressed this issue by generating gene expression data from hippocampal dentate gyrus from macaques and rats to identify clusters of co-expressed genes sensitive to GC exposure as the basis for a biologically-informed polygenic risk score (ePRS) to investigate neuropsychiatric outcomes in humans exposed to early life adversity. We used RNA-sequencing data to identify a cluster of GC-responsive genes co-expressed in the posterior dentate gyrus (pDG) of female Cynomologus monkeys and preserved in the rat model with the homologous region (the dorsal DG). In total 11395 SNPs derived from these genes (507 genes) were used to create an ePRS to explore the interaction with early life adversity on psychiatric phenotypes in human cohorts using the UK Biobank Resource and ALSPAC data sets. The biologically-informed ePRS significantly predicted psychotic behavior in adversity-exposed females as well as variation in brain volume. These findings reveal that GC exposure influences a specific group of genes in pDG, largely enriched for transcription processes and pathways related to development activity. Variations in the expression of this gene network can be used in a translational manner to predict risk for neuropsychiatric conditions and brain volume alterations after early stress exposure. These results highlight the importance of hippocampal GC-related transcriptional activity as a mediator for the effects of early life adversity on mental health outcomes. Overall design: RNA sequencing of brain regions in female macaques exposed to glucocorticoids and controls

精神疾病的发病风险极易受到环境应激因素的影响，其潜在病理机制复杂多元，目前尚未完全阐明。糖皮质激素（Glucocorticoids, GCs）是关键的应激介质，可调控转录活性并影响大脑形态，与多种精神病理过程的病理生理学机制密切相关。当前的研究难点在于，明确糖皮质激素相关的转录调控效应与人类应激相关精神病理之间的关联。本研究通过获取食蟹猴（Cynomologus monkeys）与大鼠的海马齿状回（hippocampal dentate gyrus）基因表达数据，筛选出对糖皮质激素暴露敏感的共表达基因簇，以此构建基于生物学先验知识的多基因风险评分（biologically-informed polygenic risk score, ePRS），用于探究早期生活应激暴露人群的神经精神疾病转归。我们利用RNA测序（RNA-sequencing）数据，在雌性食蟹猴的后齿状回（posterior dentate gyrus, pDG）中鉴定出一组糖皮质激素反应性共表达基因，并在具有同源脑区（背侧齿状回）的大鼠模型中验证了该基因簇的保守性。本研究共从这507个基因中筛选得到11395个单核苷酸多态性位点（single nucleotide polymorphisms, SNPs），以此构建该多基因风险评分，并依托英国生物银行（UK Biobank）与ALSPAC数据集，探索该评分与早期生活应激对人类队列精神表型的交互作用。该基于生物学先验知识的多基因风险评分可显著预测应激暴露女性的精神病性行为风险，同时也能反映脑体积的变化情况。本研究结果表明，糖皮质激素暴露可调控后齿状回中的特定基因群，该基因群主要富集于转录调控过程及发育相关通路。该基因表达网络的变异可通过转化研究的方式，用于预测早期应激暴露后神经精神疾病的发病风险及脑体积改变。上述结果凸显了海马糖皮质激素相关转录活性作为早期生活应激影响心理健康转归的中介因子的重要性。整体实验设计：对暴露于糖皮质激素的雌性食蟹猴及其对照组的脑区进行RNA测序。