ArticleEndocrine2025
Causal associations between congenital adrenal hyperplasia and neuropsychiatric conditions- a Mendelian Randomization Study.
Article in Endocrine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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Who cites it
2 citing papers in PubMed.
- The relationship between depression symptoms and cortisol levels in adolescents: the role of somatic symptoms and cognitive function.Frontiers in psychiatry · 2026Article
- Beyond endocrine features in non-classical congenital adrenal hyperplasia: a narrative review of psychoneuro-social perspectives in pediatric and adolescent patients.European journal of pediatrics · 2025Review
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Authors and funding
4 authors.
Funding
Abstract
backgroundCongenital 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.
methodsUsing 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.
resultsAdrenal-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.
conclusionOur 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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