Scholarlink

Background <p>Congenital adrenal hyperplasia (CAH), predominantly caused by 21-hydroxylase deficiency (21-OHD) due to <i>CYP21A2</i> 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 <i>CYP21A2</i> expression, reflecting CAH, differentially influences psychiatric outcomes via tissue-specific pathways.</p> Methods <p>Using two-sample Mendelian randomization (MR), we analyzed tissue-specific <i>CYP21A2</i> 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.</p> Results <p>Adrenal-derived <i>CYP21A2</i> 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 <i>CYP21A2</i> expression to elevated bioavailable testosterone (adrenal: OR = 0.972, <i>p</i> = 0.04; blood: OR = 0.983, <i>p</i> = 0.01), consistent with CAH pathophysiology.</p> Conclusion <p>Our research indicates that adrenal-driven pathways of <i>CYP21A2</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月30日

查看全文
  • Yang Liu,
  • Xiaokun Gang,
  • Yuan Gao,
  • Guixia Wang

摘要

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.