Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling

Marin D Veldic, Vincent Millischer, John D Port, Ada Man Choi Ho, Yun Fang Jia, Jennifer R. Geske, Joanna M Biernacka, Lena Backlund, Susan L. McElroy, David J. Bond, J. Carlos Villaescusa, Michelle Skime, Doo Sup Choi, Catharina Lavebratt, Martin Schalling, Mark A Frye

Research output: Contribution to journalArticle

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Abstract

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy (1H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3′ untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate–glutamine cycling, and its contribution to subphenotypes of mood disorders.

Original languageEnglish (US)
Article number149
JournalTranslational psychiatry
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Gyrus Cinguli
Glutamic Acid
Alleles
Single Nucleotide Polymorphism
Mood Disorders
Amino Acid Transport Systems
Chromosomes, Human, Pair 11
Excitatory Amino Acids
Neurobiology
Linkage Disequilibrium
Major Depressive Disorder
Homozygote
3' Untranslated Regions
Bipolar Disorder
Synaptic Transmission
Computer Simulation
Genes
Up-Regulation
Proton Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling. / Veldic, Marin D; Millischer, Vincent; Port, John D; Ho, Ada Man Choi; Jia, Yun Fang; Geske, Jennifer R.; Biernacka, Joanna M; Backlund, Lena; McElroy, Susan L.; Bond, David J.; Villaescusa, J. Carlos; Skime, Michelle; Choi, Doo Sup; Lavebratt, Catharina; Schalling, Martin; Frye, Mark A.

In: Translational psychiatry, Vol. 9, No. 1, 149, 01.12.2019.

Research output: Contribution to journalArticle

Veldic, MD, Millischer, V, Port, JD, Ho, AMC, Jia, YF, Geske, JR, Biernacka, JM, Backlund, L, McElroy, SL, Bond, DJ, Villaescusa, JC, Skime, M, Choi, DS, Lavebratt, C, Schalling, M & Frye, MA 2019, 'Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling', Translational psychiatry, vol. 9, no. 1, 149. https://doi.org/10.1038/s41398-019-0483-9
Veldic, Marin D ; Millischer, Vincent ; Port, John D ; Ho, Ada Man Choi ; Jia, Yun Fang ; Geske, Jennifer R. ; Biernacka, Joanna M ; Backlund, Lena ; McElroy, Susan L. ; Bond, David J. ; Villaescusa, J. Carlos ; Skime, Michelle ; Choi, Doo Sup ; Lavebratt, Catharina ; Schalling, Martin ; Frye, Mark A. / Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling. In: Translational psychiatry. 2019 ; Vol. 9, No. 1.
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AU - Villaescusa, J. Carlos

AU - Skime, Michelle

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