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Transl Psychiatry. 2018 Jan 10;8(1):10. doi: 10.1038/s41398-017-0056-8.

Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics.

Author information

1
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
2
Current affiliation: Assurex Health Inc, Mason, OH, USA.
3
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, School of Medicine, Mayo Clinic, Rochester, MN, USA.
4
Current affiliation: PreventionGenetics LLC, Marshfield, WI, USA.
5
Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
6
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
7
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
8
Department of Psychiatry and Behavioral Medicine, Duke University, Durham, NC, USA.
9
Department of Medicine, Duke University, Durham, NC, USA.
10
Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
11
Current affiliation: Department of Pharmacometrics, Duke Clinical Research Institute, Durham, NC, USA.
12
Department of Systems Biochemistry, Bedford VA Medical Center, Bedford, MA, UK.
13
Current affiliation: Ixcela, Inc, Bedford, MA, UK.
14
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
15
Departments of Medicine and Surgery, University of Chicago, Chicago, IL, USA.
16
Department of Psychiatry and Behavioral Medicine, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
17
Department of Medicine, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
18
Duke Institute for Brain Sciences, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
19
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. Weinshilboum.Richard@mayo.edu.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00613470.

PMID:
29317604
PMCID:
PMC5802574
DOI:
10.1038/s41398-017-0056-8
[Indexed for MEDLINE]
Free PMC Article

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