Investigation of Genetic Variants Associated with Tryptophan Metabolite Levels via Serotonin and Kynurenine Pathways in Patients with Bipolar Disorder

Claudia Pisanu, Alessio Squassina, Pasquale Paribello, Stefano Dall’acqua, Stefania Sut, Sofia Nasini, Antonella Bertazzo, Donatella Congiu, Anna Meloni, Mario Garzilli, Beatrice Guiso, Federico Suprani, Vittoria Pulcinelli, Maria Novella Iaselli, Ilaria Pinna, Giulia Somaini, Laura Arru, Carolina Corrias, Federica Pinna, Bernardo CarpinielloStefano Comai, Mirko Manchia

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants.

Original languageEnglish
Article number1127
JournalMetabolites
Volume12
Issue number11
DOIs
Publication statusPublished - 2022

Bibliographical note

Funding Information:
Funding: This study was supported, in part, by a 2017 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation to S.C.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

ASJC Scopus Subject Areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology

PubMed: MeSH publication types

  • Journal Article

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