Exploring the mediating role of potential therapeutic genes in the pathogenesis of hypopituitarism through the metabolites from a genomic perspective

Hypopituitarism is a severe endocrine disorder characterized by a partial or complete hormone deficiency in the anterior or posterior pituitary gland. Current treatment relies on hormone replacement therapy, which is unable to mimic normal physiological circadian rhythm precisely, and long-term horm...

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Published in:Mammalian genome Vol. 37; no. 1; p. 1
Main Authors: Sun, Yesheng, Zhang, Ying, Luan, Tengfei, Li, Ruichun, Cai, Dongpeng, Zhang, Wei
Format: Journal Article
Language:English
Published: New York Springer US 01.12.2026
Springer Nature B.V
Subjects:
Amino acids
Animal Genetics and Genomics
Bayesian analysis
Biomedical and Life Sciences
Carbohydrates
Cell Biology
Cerebrospinal fluid
Circadian rhythms
Endocrine disorders
Gene expression
Genetic Predisposition to Disease
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genomics
Hormone replacement therapy
Hormones
Human Genetics
Humans
Hypopituitarism
Hypopituitarism - genetics
Hypopituitarism - metabolism
Hypopituitarism - pathology
Hypothalamus
Life Sciences
Mathematical models
Mendelian Randomization Analysis
Metabolism
Metabolites
Mutation
Pathogenesis
Peptides
Pituitary (anterior)
Pituitary (posterior)
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Statistical analysis
Statistics
Therapeutic targets
Variables
ISSN:0938-8990, 1432-1777, 1432-1777
Online Access:Get full text
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Summary:Hypopituitarism is a severe endocrine disorder characterized by a partial or complete hormone deficiency in the anterior or posterior pituitary gland. Current treatment relies on hormone replacement therapy, which is unable to mimic normal physiological circadian rhythm precisely, and long-term hormone replacement therapy can result in a variety of adverse effects. This study aimed to identify potential drug targets and clarify the mechanisms underlying hypopituitarism. To identify potential therapeutic targets for hypopituitarism, summary statistics from expression quantitative trait loci (eQTL) datasets, serum and cerebrospinal fluid (CSF) metabolites, and hypopituitarism genome-wide association study (GWAS) data were integrated for analysis. Two-sample Mendelian randomization (MR) analysis was performed to identify causal genes associated with hypopituitarism. Subsequently, the relationship between serum and CSF metabolites and hypopituitarism was investigated. Finally, a two-step MR analysis explored the mediation of these metabolites in the causal gene-hypopituitarism pathway, quantifying both direct and mediation effects. A total of 20 genes associated with hypopituitarism were identified, with RMI2, UBAC1, and GLIPR1 further validated by Bayesian colocalization, and the causal relationship between CHST13, GABPB1-AS1, GLIPR1L2, RNF14, and hypopituitarism was confirmed by summary data-based MR (SMR) and HEIDI analysis. Additionally, 34 serum metabolites and 8 CSF metabolites were causally associated with hypopituitarism. Furthermore, mediation MR analysis demonstrated that 1-Methyl-4-imidazoleacetate was the only mediator, explaining 4.35% ( P  = 0.049) of the total effect of UBAC1 on increased hypopituitarism susceptibility. This study identified RMI2, UBAC1, CHST13, GABPB1-AS1, GLIPR1L2, RNF14, and GLIPR1 as potentially causal genes in the pathogenesis of hypopituitarism. Furthermore, UBAC1-mediated regulation of serum metabolites may contribute to promoting hypopituitarism progression, indicating that UBAC1 is a candidate gene warranting further functional validation. Future directions could include assessing UBAC1 expression in pituitary/hypothalamus single-cell RNA-seq or in vivo models. 
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ISSN:0938-8990
1432-1777
1432-1777
DOI:10.1007/s00335-025-10169-1