Uncovering associations between mental illness diagnosis, nitric oxide synthase gene variation, and peripheral nitric oxide concentration

Rhiannon V McNeill; Christopher Kehrwald; Murielle Brum; Katrin Knopf; Nathalie Brunkhorst-Kanaan; Semra Etyemez; Carolin Koreny; Robert A Bittner; Florian Freudenberg; Sabine Herterich; Andreas Reif; Sarah Kittel-Schneider

doi:10.1016/j.bbi.2022.01.006

Uncovering associations between mental illness diagnosis, nitric oxide synthase gene variation, and peripheral nitric oxide concentration

Brain Behav Immun. 2022 Mar:101:275-283. doi: 10.1016/j.bbi.2022.01.006. Epub 2022 Jan 15.

Affiliations

¹ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, University of Würzburg, D-97080 Würzburg, Germany; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe-University Frankfurt, Heinrich-Hoffmann-Str. 10, D-60528 Frankfurt/Main, Germany. Electronic address: McNeill_R@ukw.de.
² Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe-University Frankfurt, Heinrich-Hoffmann-Str. 10, D-60528 Frankfurt/Main, Germany.
³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe-University Frankfurt, Heinrich-Hoffmann-Str. 10, D-60528 Frankfurt/Main, Germany; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, University of Würzburg, D-97080 Würzburg, Germany.
⁵ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe-University Frankfurt, Heinrich-Hoffmann-Str. 10, D-60528 Frankfurt/Main, Germany; Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society, Frankfurt am Main, Germany.
⁶ Central Laboratory, University Hospital, University of Würzburg, D-97080 Würzburg, Germany.
⁷ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, University of Würzburg, D-97080 Würzburg, Germany; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe-University Frankfurt, Heinrich-Hoffmann-Str. 10, D-60528 Frankfurt/Main, Germany.

PMID: 35041938
DOI: 10.1016/j.bbi.2022.01.006

Abstract

Nitric oxide (NO) signalling has been implicated in the pathogenesis of several mental illnesses; however, its specific contribution remains unclear. We investigated whether peripheral NO concentration is associated with specific diagnoses, and whether there is a correlation with genetic variation in NO synthase (NOS) genes. We included 185 participants in the study; 52 healthy controls, 43 major depressive disorder (MDD) patients, 41 bipolar disorder (BPD) patients, and 49 schizophrenia (SCZ) patients. Clinical, genetic, and biochemical data were collected at admission to a psychiatric hospital and at discharge. Serum was used to quantify concentration of the stable NO metabolites nitrite and nitrate. Individuals were genotyped for the NOS1 exon 1f variable number of tandem repeats 1 (VNTR1) polymorphism, and single nucleotide polymorphisms (SNPs) in the NOS1, NOS1AP and NOS3 genes. At admission, SCZ patients were found to have significantly higher peripheral NO metabolite (NO_x-) concentrations compared to healthy controls, MDD and BPD patients. NOS1 exon 1f VNTR1 short allele carriers were found to have significantly increased NO_x- concentration. Moreover, this result was still significant in patients even at discharge. The data also revealed that patients who did not remit in their depressive symptoms had significantly increased NO_x- concentration compared to remitters at discharge, supported by the finding of a significant positive correlation between depression symptom severity and NO_x- concentration. Taken together, it is possible that elevated peripheral NO_x- concentration is associated with increased severity of psychopathology, potentially due to NOS1 exon1f VNTR1 genotype. Our results further implicate NO signalling in mental illness pathogenesis, supporting its possible use as a peripheral biomarker, and imply that NOS genotype may play a significant role in regulating peripheral NO_x- concentration.

Keywords: Bipolar disorder; Genetics; Major depressive disorder; Nitric oxide; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Depressive Disorder, Major* / genetics
Genotype
Humans
Mental Disorders*
Nitric Oxide / metabolism
Nitric Oxide Synthase Type I* / genetics
Nitric Oxide Synthase Type III / genetics
Polymorphism, Single Nucleotide

Substances

Adaptor Proteins, Signal Transducing
NOS1AP protein, human
Nitric Oxide
NOS3 protein, human
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type III