Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder

Metabolomics-informed genomics

Duan Liu, Balmiki Ray, Drew R. Neavin, Jiabin Zhang, Arjun P. Athreya, Joanna M. Biernacka, William V. Bobo, Daniel K. Hall-Flavin, Michelle K. Skime, Hongjie Zhu, Gregory D. Jenkins, Anthony Batzler, Krishna R. Kalari, Felix Boakye-Agyeman, Wayne R. Matson, Swati S. Bhasin, Taisei Mushiroda, Yusuke Nakamura, Michiaki Kubo, Ravishankar K. Iyer & 4 others Liewei Wang, Mark A. Frye, Rima Kaddurah-Daouk, Richard M. Weinshilboum

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article number56
JournalTranslational psychiatry
Volume8
Issue number1
DOIs
Publication statusPublished - 01-12-2018

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beta-Defensins
Kynurenine
Aryl Hydrocarbon Receptors
Metabolomics
Major Depressive Disorder
Genomics
Genome-Wide Association Study
Depression
Quantitative Trait Loci
Single Nucleotide Polymorphism
Validation Studies
Enzymes
Tryptophan
Astrocytes
Antidepressive Agents
Genes
Tyrosine
Culture Media
Lipopolysaccharides
Hepatocytes

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Liu, Duan ; Ray, Balmiki ; Neavin, Drew R. ; Zhang, Jiabin ; Athreya, Arjun P. ; Biernacka, Joanna M. ; Bobo, William V. ; Hall-Flavin, Daniel K. ; Skime, Michelle K. ; Zhu, Hongjie ; Jenkins, Gregory D. ; Batzler, Anthony ; Kalari, Krishna R. ; Boakye-Agyeman, Felix ; Matson, Wayne R. ; Bhasin, Swati S. ; Mushiroda, Taisei ; Nakamura, Yusuke ; Kubo, Michiaki ; Iyer, Ravishankar K. ; Wang, Liewei ; Frye, Mark A. ; Kaddurah-Daouk, Rima ; Weinshilboum, Richard M. / Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder : Metabolomics-informed genomics. In: Translational psychiatry. 2018 ; Vol. 8, No. 1.
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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.",
author = "Duan Liu and Balmiki Ray and Neavin, {Drew R.} and Jiabin Zhang and Athreya, {Arjun P.} and Biernacka, {Joanna M.} and Bobo, {William V.} and Hall-Flavin, {Daniel K.} and Skime, {Michelle K.} and Hongjie Zhu and Jenkins, {Gregory D.} and Anthony Batzler and Kalari, {Krishna R.} and Felix Boakye-Agyeman and Matson, {Wayne R.} and Bhasin, {Swati S.} and Taisei Mushiroda and Yusuke Nakamura and Michiaki Kubo and Iyer, {Ravishankar K.} and Liewei Wang and Frye, {Mark A.} and Rima Kaddurah-Daouk and Weinshilboum, {Richard M.}",
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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 2018, 'Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: Metabolomics-informed genomics', Translational psychiatry, vol. 8, no. 1, 56. https://doi.org/10.1038/s41398-017-0056-8

Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder : Metabolomics-informed genomics. / Liu, Duan; Ray, Balmiki; Neavin, Drew R.; Zhang, Jiabin; Athreya, Arjun P.; Biernacka, Joanna M.; Bobo, William V.; Hall-Flavin, Daniel K.; Skime, Michelle K.; Zhu, Hongjie; Jenkins, Gregory D.; Batzler, Anthony; Kalari, Krishna R.; Boakye-Agyeman, Felix; Matson, Wayne R.; Bhasin, Swati S.; Mushiroda, Taisei; Nakamura, Yusuke; Kubo, Michiaki; Iyer, Ravishankar K.; Wang, Liewei; Frye, Mark A.; Kaddurah-Daouk, Rima; Weinshilboum, Richard M.

In: Translational psychiatry, Vol. 8, No. 1, 56, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder

T2 - Metabolomics-informed genomics

AU - Liu, Duan

AU - Ray, Balmiki

AU - Neavin, Drew R.

AU - Zhang, Jiabin

AU - Athreya, Arjun P.

AU - Biernacka, Joanna M.

AU - Bobo, William V.

AU - Hall-Flavin, Daniel K.

AU - Skime, Michelle K.

AU - Zhu, Hongjie

AU - Jenkins, Gregory D.

AU - Batzler, Anthony

AU - Kalari, Krishna R.

AU - Boakye-Agyeman, Felix

AU - Matson, Wayne R.

AU - Bhasin, Swati S.

AU - Mushiroda, Taisei

AU - Nakamura, Yusuke

AU - Kubo, Michiaki

AU - Iyer, Ravishankar K.

AU - Wang, Liewei

AU - Frye, Mark A.

AU - Kaddurah-Daouk, Rima

AU - Weinshilboum, Richard M.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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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