Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder

Abstract

Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. [GC] conferred an OR maximal for schizophrenia alone (4.84, p= 0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melantropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism.

Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

“…For example, specific genotypes are thought to result in increases in tryptophan dioxygenase mRNA and protein in the brains of persons with schizophrenia, which lead to elevations in L-KYN and KYNA concentration. [21][22][23][24] Indeed, levels of KYNA in the brain are normally very low early in life, 40 thus excessive blockade of NMDA-Rs and/or a7 nAChRs by increased KYNA concentration could alter brain development in persons with schizophrenia because these receptors are critically involved in neural plasticity and development. 4,5 Whether the cellular and physiological effects of KYNA are mediated primarily through NMDA-Rs or a7 nAChRs remains to be conclusively resolved.…”

“…Indeed, recent studies indicate that genotypic alterations may underlie changes in KYNA concentration associated with schizophrenia. [21][22][23][24] One implication of these findings is that exposure to high levels of KYNA may begin early in life. It is well established that both acetylcholine and glutamate play critical roles in normal brain development [25][26][27] and that NMDA-Rs and a7 nAChRs are involved in synaptic plasticity and neural development.…”

Placental Source for 5-HT that Tunes Fetal Brain Development

“…Thus, like other placentaderived molecules (eg, growth factors), placental 5-HT output could be affected by both genetic (the embryo and placenta are genetically identical) and environmental disturbances that are known to increase risk for mental illnesses. In fact, altered tryptophan metabolism during pregnancy in mice has long-term functional consequences in the offspring, and has been implicated in increasing the risk for schizophrenia, bipolar disorder, and autism in humans (Miller et al, 2009). Although long-term follow-up studies are needed, prenatal exposure to SSRI antidepressants induces an array of disturbances in childhood.…”

The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case–control sample

“…They analyzed one SNP in each of six genes in the kynurenine pathway and among the analyzed SNPs was rs133073, which was significantly associated with schizophrenia in the present study. Miller et al (2009) When analyzing the sexes separately, only one SNP (rs133076) was significant in women, but in men the associations were 10 times stronger (lower P values) than the associations found in the analysis of all patients indicating that variations in MCHR1 have sex-specific influences on disease risk. The SNP rs133072, which was only significantly associated with schizophrenia in men (Table 2) is nonsynonymous encoding either an asparagine or an aspartic acid amino acid residue in the extracellular part of MCHR-1.…”

“…A recent study by Miller et al (2009) has also found MCHR1 variation to be involved in schizophrenia. They analyzed one SNP in each of six genes in the kynurenine pathway and among the analyzed SNPs was rs133073, which was significantly associated with schizophrenia in the present study.…”