B. Ray,1 F. Boakye-Agyeman,1 H. Zhu,2 J. Biernacka,1 D. Liu,1 A. Taddei,1 G. Jenkins,1 K. Kalari,1 T. Mushiroda,3 M. Kubo,3 Y. Nakamura,4 W. Matson,5 L. Wang,1 R. Kaddurah-Daouk,2 R. M. Weinshilboum1; 1Mayo Clinic, Rochester, MN, 2Pharmacometabolomics Research Network, Duke University School of Medicine, Durham, NC, 3RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, 4The University of Chicago, Chicago, IL, 5Bedford VA Research Corporation, Inc., Bedford, MA
BACKGROUND: Major depressive disorder (MDD) is the most common psychiatric disease worldwide and contributes to both morbidity and mortality. To evaluate genetic variation associated with MDD as well as response to the SSRI therapy of this disease, we employed a pharmacometabolomics-informed pharmacogenomic (PGx) research strategy.
METHODS: Both baseline and post-treatment plasma samples from 306 patients enrolled in the Mayo SSRI PGx study were analyzed for 37 metabolites with an LCECA platform. Genome-wide association analyses of the metabolites were performed both at baseline and after SSRI therapy. Since the balance between serotonin and kynurenine (KYN) may be important in psychiatric disorders, we evaluated genetic variants associated with plasma KYN levels.
RESULTS: We observed genetic variants across AHR (top SNP rs17137566; p=6.22E-06) that were associated with baseline KYN levels. These SNPs were eQTLs for AHR. Functional evaluation using human glioma and human iPSC-derived neurons showed that knocking down AHR increased both mRNA and protein levels of the AHR-repressor (AHRR) and those of genes (IDO1 and TDO2) encoding the rate limiting enzymes for KYN synthesis. Levels of secreted KYN in conditioned media for these cells were also increased. Levels of these same mRNAs and KYN levels were decreased after over-expression of AHR. AHRR over-expression resulted in several fold increases in the AHR, IDO1, TDO2 mRNA expression and KYN levels, possibly indicating a feedback loop between AHR and AHRR. AHRR might act as a transcription factor for IDO1 and TDO2.
CONCLUSION: These findings indicate that genetic variance in AHR could be pharmacogenomic markers for MDD or MDD response to therapy mediated through the transcriptional regulation of AHRR, IDO1 and TDO2.