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.
Bibliographical noteFunding Information:
This work was supported by the National Institute of Mental Health RO1MH079261, National Alliance for Research in Depression and Schizophrenia (NARSAD) Independent Investigator Award, the Marriott Foundation and Mayo Clinic Genomics of Addition to Dr. Frye, and by the Mayo Foundation for Medical Education and Research as well as the J. Willard and Alice S. Marriott Foundation grant to Dr. Veldic. The project was supported by grants from the Karolinska Institutet, the KI-Mayo Collaboration (MV, CL, VM), the Swedish Research Council (2016-02653 (MS); 2014-10171 (CL)), the Swedish Brain Foundation (FO2017-0129 (CL); FO2018-0141 (CL)) and grants from the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and the Karolinska Institutet (SLL20170292 (CL)). Dr. Choi is a scientific advisory board member to Peptron Inc. Dr. Frye is a consultant (for Mayo Clinic) to Janssen, Mitsubishi Tanabe Pharma Corporation, Myriad, Sunovion, and Teva Pharmaceuticals. None of this funding contributed to work carried out in this study.