SU3. Preliminary Study for Association of Genome-Wide Significant Glutamate Receptor Schizophrenia Risk Variants With Clozapine Response
Bibliographic record
Abstract
Background: Schizophrenia is a lifelong debilitating mental illness often characterized by hallucinations, delusions, and disorganized thought and behavior. Currently, antipsychotic medications serve as the best treatment option for schizophrenia, but clinical responses to antipsychotic medications are highly variable. Therefore, the demand for reliable biological predictors is high. A glutamate and N-methyl-d-asparate (NMDA) receptor hypofunction model based on pharmacologic and genetic studies have been suggested as an approach to study the pharmacogenetics of antipsychotic medications. Previous studies have shown clozapine (CLZ) displaces NMDAR antagonists and enhances NMDAR mediated neurotransmission. Previously, our group (Taylor et al, 2016) investigated 8 SNPs in the NMDAR subunit gene GRIN2B with response to CLZ and one marker (rs1072388) was nominally significant. Taylor et al (in press) more recently found the glycine transporter 1 gene (SLC6A9, rs16831558) exhibited an allele dose-dependent improvement in the positive symptoms of CC-homozygotes compared to T-allele carriers (Puncorrected = .008, Pcorrected = .08). In our current study, we examined the GRIN2A receptor gene that was genome-wide significant in the GWAS of schizophrenia by Ripke et al (2014). A SNP marker from GRIN2A (rs992266789) and one from the glutamate receptor ionotropic delta 2 (GRID2, rs1875705) were selected for our association study of CLZ treatment response. Methods: We investigated rs9922678 and rs1875705 in relation to CLZ treatment response in a prospective study consisting of 170 Caucasian patients treated with CLZ for 6 months. Treatment response was evaluated using the 18-item Brief Psychiatric Rating Scale (BPRS), using either responder vs nonresponder status or continuous change scores. Baseline score was included as a covariate. All statistical analyses were performed using IBM SPSS. Results: No significant association was observed for rs9922678 and rs1875705 with BPRS total score and responder vs nonresponder status under genotypic, allelic, and additive models. Conclusion: Although no significant results were obtained from our current study, there is still strong neurobiological evidence suggesting involvement of the glutamate system in CLZ action. Additional glutamate system genes and multiple markers should be investigated. Further studies with greater sample size are required before firm conclusions can be drawn. In addition, it would be helpful to investigate other phenotypes such as cognition and tardive dyskinesia because glutamate neurotransmission also plays a role in these areas.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.032 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".