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

Publication ,  Journal Article
Liu, D; Ray, B; Neavin, DR; Zhang, J; Athreya, AP; Biernacka, JM; Bobo, WV; Hall-Flavin, DK; Skime, MK; Zhu, H; Jenkins, GD; Batzler, A ...
Published in: Transl Psychiatry
January 10, 2018

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.

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Published In

Transl Psychiatry

DOI

EISSN

2158-3188

Publication Date

January 10, 2018

Volume

8

Issue

1

Start / End Page

10

Location

United States

Related Subject Headings

  • beta-Defensins
  • Signal Transduction
  • Severity of Illness Index
  • Receptors, Aryl Hydrocarbon
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Metabolomics
  • Linear Models
  • Kynurenine
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Liu, D., Ray, B., Neavin, D. R., Zhang, J., Athreya, A. P., Biernacka, J. M., … Weinshilboum, R. M. (2018). Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Transl Psychiatry, 8(1), 10. https://doi.org/10.1038/s41398-017-0056-8
Liu, Duan, Balmiki Ray, Drew R. Neavin, Jiabin Zhang, Arjun P. Athreya, Joanna M. Biernacka, William V. Bobo, et al. “Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics.Transl Psychiatry 8, no. 1 (January 10, 2018): 10. https://doi.org/10.1038/s41398-017-0056-8.
Liu D, Ray B, Neavin DR, Zhang J, Athreya AP, Biernacka JM, et al. Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Transl Psychiatry. 2018 Jan 10;8(1):10.
Liu, Duan, et al. “Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics.Transl Psychiatry, vol. 8, no. 1, Jan. 2018, p. 10. Pubmed, doi:10.1038/s41398-017-0056-8.
Liu D, Ray B, Neavin DR, Zhang J, Athreya AP, Biernacka JM, Bobo WV, Hall-Flavin DK, Skime MK, Zhu H, Jenkins GD, Batzler A, Kalari KR, Boakye-Agyeman F, Matson WR, Bhasin SS, Mushiroda T, Nakamura Y, Kubo M, Iyer RK, Wang L, Frye MA, Kaddurah-Daouk R, Weinshilboum RM. Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Transl Psychiatry. 2018 Jan 10;8(1):10.

Published In

Transl Psychiatry

DOI

EISSN

2158-3188

Publication Date

January 10, 2018

Volume

8

Issue

1

Start / End Page

10

Location

United States

Related Subject Headings

  • beta-Defensins
  • Signal Transduction
  • Severity of Illness Index
  • Receptors, Aryl Hydrocarbon
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Metabolomics
  • Linear Models
  • Kynurenine
  • Humans