Risk-Conferring Glutamatergic Genes and Brain Glutamate Plus Glutamine in Schizophrenia

Abstract

BackgroundThe proton magnetic resonance spectroscopy (1H-MRS) signals from glutamate (or the combined glutamate and glutamine signal—Glx) have been found to be greater in various brain regions in people with schizophrenia. Recently, the Psychiatric Genetics Consortium reported that several common single-nucleotide polymorphisms (SNPs) in glutamate-related genes confer increased risk of schizophrenia. Here, we examined the relationship between presence of these risk polymorphisms and brain Glx levels in schizophrenia.Methods1H-MRS imaging data from an axial, supraventricular tissue slab were acquired in 56 schizophrenia patients and 67 healthy subjects. Glx was measured in gray matter (GM) and white matter (WM) regions. The genetic data included six polymorphisms genotyped across an Illumina 5M SNP array. Only three of six glutamate as well as calcium-related SNPs were available for examination. These included three glutamate-related polymorphisms (rs10520163 in CLCN3, rs12704290 in GRM3, and rs12325245 in SLC38A7), and three calcium signaling polymorphisms (rs1339227 in RIMS1, rs7893279 in CACNB2, and rs2007044 in CACNA1C). Summary risk scores for the three glutamate and the three calcium polymorphisms were calculated.ResultsGlx levels in GM positively correlated with glutamate-related genetic risk score but only in younger (≤36 years) schizophrenia patients (p = 0.01). Glx levels did not correlate with calcium risk scores. Glx was higher in the schizophrenia group compared to levels in controls in GM and WM regardless of age (p < 0.001).ConclusionElevations in brain Glx are in part, related to common allelic variants of glutamate-related genes known to increase the risk for schizophrenia. Since the glutamate risk scores did not differ between groups, some other genetic or environmental factors likely interact with the variability in glutamate-related risk SNPs to contribute to an increase in brain Glx early in the illness.

Heritability of cerebral glutamate levels and their association with schizophrenia spectrum disorders: a 1[H]-spectroscopy twin study

“…The finding of common genetic influences on glutamate levels in the thalamus and disease in our study is supported by a report of higher glx levels in the thalamus of subjects at increased familial risk for schizophrenia [33], and a recent study linking higher glx levels to glutamate-related genes associated with risk for schizophrenia [5]. The current heritability estimates are in line with the heritability estimate of glx in the thalamus reported in a twin study in children with autism and controls [34], suggesting a generalizability of the heritability estimate across populations.…”

“…Schizophrenia constitutes a heterogeneous phenotype with a complex etiology, but clinical, animal, and genetic studies have supported the involvement of glutamate metabolism in its pathophysiology [1][2][3][4][5]. However, the extent to which aberrant glutamate concentration and disease liability are founded in common genes remains to be established.…”

Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders

“…These observations have been reported in patients with SCZ, especially in subjects at risk of psychosis [178].…”

Single-step genome-wide association study for social genetic effects and direct genetic effects on growth in Landrace pigs

“…Another QTL window at 19.9-20.9 Mb, which accounted for 0.87% of additive genetic variance, contained SLC38A7, which encodes solute carrier family 38 member 7 (also known as the SNAT7 protein). Hägglund et al reported that SLC38A7 is a sodium-coupled amino acid transporter in glutamatergic neurons in the brain 40 , and it has been implicated as a risk-conferring glutamatergic gene in schizophrenia 41 . In the QTL region of SSC6:70.8-71.8 Mb, the mammalian target of rapamycin (mTOR) gene was found to be associated with SGE on ADG.…”