Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia

Kira Griffiths, Sophie E. Smart, Gareth J. Barker, Bill Deakin, Stephen M. Lawrie, Shon Lewis, David J. Lythgoe, Antonio F. Pardiñas, Krishna Singh, Scott Semple, James T.R. Walters, Stephen R. Williams, Alice Egerton, James H. MacCabe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Dysfunction of glutamate neurotransmission has been implicated in the
pathophysiology of schizophrenia and may be particularly relevant in severe,
treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated
with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β = -0.25, 95% CI = -0.49, -0.02, competitive p=0.03). When SNPs were weight by associations with non-treatment resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β = 0.05, 95% CI = -0.18, 0.27, competitive p=0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment resistant schizophrenia.
Original languageEnglish
Pages (from-to)152-159
Number of pages8
JournalSchizophrenia Research
Volume260
Early online date30 Aug 2023
DOIs
Publication statusPublished - Oct 2023

Keywords

  • anterior cingulate cortex
  • Glutamate
  • magnetic resonance spectroscopy
  • schizophrenia

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