Liu Yang, Gang Xiaokun, Gao Yuan, Wang Guixia
Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, China.
Endocrine. 2025 Apr 30. doi: 10.1007/s12020-025-04237-4.
Congenital adrenal hyperplasia (CAH), predominantly caused by 21-hydroxylase deficiency (21-OHD) due to CYP21A2 mutations, disrupts cortisol synthesis and adrenal androgen homeostasis. Observational studies suggest CAH patients exhibit elevated risks of neuropsychiatric disorders, but causal mechanisms remain unestablished. We hypothesized that reduced CYP21A2 expression, reflecting CAH, differentially influences psychiatric outcomes via tissue-specific pathways.
Using two-sample Mendelian randomization (MR), we analyzed tissue-specific CYP21A2 expression quantitative trait loci (eQTLs) from adrenal (GTEx v8) and whole blood (GTEx v8 and eQTLGen meta-analysis). Genetic instruments were validated via positive control MR with classical CAH biomarkers. Associations with ten neuropsychiatric disorders were assessed using inverse-variance-weighted MR, supplemented by sensitivity analyses (LCV, SMR) and LD score regression.
Adrenal-derived CYP21A2 downregulation reduced Alzheimer's disease (AD) risk (discovery: OR = 1.245, replication: OR = 1.100) but increased autism spectrum disorder (ASD) susceptibility (discovery: OR = 0.766, replication: OR = 0.659). Conversely, blood-derived eQTLs showed opposing effects that decreased ASD risk (discovery: OR = 1.072, replication: OR = 1.071) and elevated AD risk (OR = 0.968 for both discovery and replication). Both tissues linked reduced CYP21A2 expression to elevated bioavailable testosterone (adrenal: OR = 0.972, p = 0.04; blood: OR = 0.983, p = 0.01), consistent with CAH pathophysiology.
Our research indicates that adrenal-driven pathways of CYP21A2 deficiency may reduce the risk of AD while increasing the ASD risk. These findings underscore the pivotal role of endocrine mechanisms in the pathogenesis of neuropsychiatric disorders and advocate for personalized CAH management integrating mental health monitoring.
先天性肾上腺皮质增生症（CAH）主要由CYP21A2突变导致的21-羟化酶缺乏（21-OHD）引起，会破坏皮质醇合成和肾上腺雄激素稳态。观察性研究表明，CAH患者患神经精神疾病的风险升高，但因果机制尚未明确。我们假设，反映CAH的CYP21A2表达降低会通过组织特异性途径对精神疾病结局产生不同影响。
我们使用两样本孟德尔随机化（MR）方法，分析了来自肾上腺（GTEx v8）和全血（GTEx v8和eQTLGen荟萃分析）的组织特异性CYP21A2表达定量性状位点（eQTL）。通过与经典CAH生物标志物进行阳性对照MR验证遗传工具。使用逆方差加权MR评估与十种神经精神疾病的关联，并辅以敏感性分析（LCV、SMR）和连锁不平衡评分回归。
肾上腺来源的CYP21A2下调降低了阿尔茨海默病（AD）风险（发现阶段：OR = 1.245，复制阶段：OR = 1.100），但增加了自闭症谱系障碍（ASD）易感性（发现阶段：OR = 0.766，复制阶段：OR = 0.659）。相反，血液来源的eQTL显示出相反的作用，即降低了ASD风险（发现阶段：OR = 1.072，复制阶段：OR = 1.071）并增加了AD风险（发现和复制阶段均为OR = 0.968）。两种组织均将CYP21A2表达降低与生物可利用睾酮升高联系起来（肾上腺：OR = 0.972，p = 0.04；血液：OR = 0.983，p = 0.01），这与CAH病理生理学一致。
我们的研究表明，肾上腺驱动的CYP21A2缺乏途径可能会降低AD风险，同时增加ASD风险。这些发现强调了内分泌机制在神经精神疾病发病机制中的关键作用，并提倡在CAH管理中纳入心理健康监测的个性化方案。
