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Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics
- Source :
- Translational Psychiatry, Translational Psychiatry, Vol 8, Iss 1, Pp 1-13 (2018)
- Publication Year :
- 2017
-
Abstract
- Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for sub-classifying MDD and antidepressant therapy by genome-wide association studies (GWAS) alone have generally yielded disappointing results. We applied a metabolomics-informed genomic research strategy to study the contribution of genetic variation to MDD pathophysiology by assaying 31 metabolites, including compounds from the tryptophan, tyrosine, and purine pathways, in plasma samples from 290 MDD patients. Associations of metabolite concentrations with depressive symptoms were determined, followed by GWAS for selected metabolites and functional validation studies of the genes identified. Kynurenine (KYN), the baseline plasma metabolite that was most highly associated with depressive symptoms, was negatively correlated with severity of those symptoms. GWAS for baseline plasma KYN concentrations identified SNPs across the beta-defensin 1 (DEFB1) and aryl hydrocarbon receptor (AHR) genes that were cis-expression quantitative trait loci (eQTLs) for DEFB1 and AHR mRNA expression, respectively. Furthermore, the DEFB1 locus was associated with severity of MDD symptoms in a larger cohort of 803 MDD patients. Functional studies demonstrated that DEFB1 could neutralize lipopolysaccharide-stimulated expression of KYN-biosynthesizing enzymes in monocytic cells, resulting in altered KYN concentrations in the culture media. In addition, we demonstrated that AHR was involved in regulating the expression of enzymes in the KYN pathway and altered KYN biosynthesis in cell lines of hepatocyte and astrocyte origin. In conclusion, these studies identified SNPs that were cis-eQTLs for DEFB1 and AHR and, which were associated with variation in plasma KYN concentrations that were related to severity of MDD symptoms.
- Subjects :
- 0301 basic medicine
beta-Defensins
Metabolite
Quantitative Trait Loci
Genome-wide association study
Single-nucleotide polymorphism
Pharmacology
Quantitative trait locus
Polymorphism, Single Nucleotide
Severity of Illness Index
Article
lcsh:RC321-571
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Basic Helix-Loop-Helix Transcription Factors
Medicine
Humans
Metabolomics
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Biological Psychiatry
Kynurenine
Genetic association
Depressive Disorder, Major
biology
business.industry
Genomics
Aryl hydrocarbon receptor
medicine.disease
3. Good health
Psychiatry and Mental health
030104 developmental biology
chemistry
Receptors, Aryl Hydrocarbon
biology.protein
Linear Models
Major depressive disorder
business
030217 neurology & neurosurgery
Biomarkers
Genome-Wide Association Study
Signal Transduction
Subjects
Details
- ISSN :
- 21583188
- Volume :
- 8
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Translational psychiatry
- Accession number :
- edsair.doi.dedup.....1893fec062b1f9e57fcd670a36a0ee06