Causal associations between congenital adrenal hyperplasia and neuropsychiatric conditions- a Mendelian Randomization Study.

IF 3 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Endocrine Pub Date : 2025-04-30 DOI:10.1007/s12020-025-04237-4

Yang Liu, Xiaokun Gang, Yuan Gao, Guixia Wang

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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先天性肾上腺增生与神经精神疾病的因果关系——孟德尔随机研究。

背景：先天性肾上腺增生症（CAH）主要由CYP21A2突变引起的21-羟化酶缺乏症（21-OHD）引起，破坏皮质醇合成和肾上腺雄激素稳态。观察性研究表明，CAH患者出现神经精神疾病的风险升高，但因果机制尚未确定。我们假设，反映CAH的CYP21A2表达减少，通过组织特异性途径对精神预后产生差异影响。方法：采用双样本孟德尔随机化（MR）方法，分析肾上腺（GTEx v8）和全血（GTEx v8和eQTLGen荟萃分析）中组织特异性CYP21A2表达数量性状位点（eQTLs）。遗传仪器通过经典CAH生物标志物阳性对照MR进行验证。使用反方差加权MR评估与10种神经精神疾病的相关性，辅以敏感性分析（LCV， SMR）和LD评分回归。结果：肾上腺源性CYP21A2下调降低了阿尔茨海默病（AD）的风险（发现：OR = 1.245，复制：OR = 1.100），但增加了自闭症谱系障碍（ASD）的易感性（发现：OR = 0.766，复制：OR = 0.659）。相反，血液来源的eqtl表现出相反的作用，即降低ASD风险（发现：OR = 1.072，复制：OR = 1.071）和升高AD风险（发现和复制均OR = 0.968）。两种组织中CYP21A2表达降低与生物可利用睾酮升高有关(肾上腺：OR = 0.972, p = 0.04；血：OR = 0.983, p = 0.01)，与CAH病理生理一致。结论：我们的研究表明，CYP21A2缺乏的肾上腺驱动通路可能降低AD的风险，同时增加ASD的风险。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，并提倡将精神健康监测纳入CAH的个性化管理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Endocrine ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

5.40%

发文量

295

审稿时长

1.5 months

期刊介绍： Well-established as a major journal in today’s rapidly advancing experimental and clinical research areas, Endocrine publishes original articles devoted to basic (including molecular, cellular and physiological studies), translational and clinical research in all the different fields of endocrinology and metabolism. Articles will be accepted based on peer-reviews, priority, and editorial decision. Invited reviews, mini-reviews and viewpoints on relevant pathophysiological and clinical topics, as well as Editorials on articles appearing in the Journal, are published. Unsolicited Editorials will be evaluated by the editorial team. Outcomes of scientific meetings, as well as guidelines and position statements, may be submitted. The Journal also considers special feature articles in the field of endocrine genetics and epigenetics, as well as articles devoted to novel methods and techniques in endocrinology. Endocrine covers controversial, clinical endocrine issues. Meta-analyses on endocrine and metabolic topics are also accepted. Descriptions of single clinical cases and/or small patients studies are not published unless of exceptional interest. However, reports of novel imaging studies and endocrine side effects in single patients may be considered. Research letters and letters to the editor related or unrelated to recently published articles can be submitted. Endocrine covers leading topics in endocrinology such as neuroendocrinology, pituitary and hypothalamic peptides, thyroid physiological and clinical aspects, bone and mineral metabolism and osteoporosis, obesity, lipid and energy metabolism and food intake control, insulin, Type 1 and Type 2 diabetes, hormones of male and female reproduction, adrenal diseases pediatric and geriatric endocrinology, endocrine hypertension and endocrine oncology.