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Before genome-wide studies became affordable, researchers hunted for schizophrenia'sA long-term mental illness involving episodes of psychosis such as hallucinations and delusions.Read more → cause one gene at a time, and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were two of the most-studied candidates because both sit inside the glutamate signalling system thought to be disrupted in the illness. Their story matters for the exam because it illustrates why psychiatric genetics moved from single candidate genes to a polygenic model, where many common variants each contribute a small effect.

Neuregulin 1 (NRG1) signals through the ErbB4 receptor, and this signalling modulates NMDA-type glutamate receptor function and synaptic plasticity — the strengthening or weakening of connections between neurons with use. Dysbindin, encoded by DTNBP1, is part of the BLOC-1 protein complex that helps package and release glutamate-containing vesicles at the synapseThe tiny gap between two nerve cells where a chemical signal passes from one to the other.Read more →. For example, reduced dysbindin expression has been reported in post-mortem prefrontal cortexThe front part of the brain responsible for planning, judgement and controlling impulses.Read more → tissue from people with schizophreniaA long-term mental illness involving episodes of psychosis such as hallucinations and delusions.Read more → — a chronic psychotic disorder marked by delusionsA fixed false belief, held with total conviction, that is not shared by the person's culture and is not changed by evidence against it.Read more →, altered perception, and disorganised thinking — consistent with a glutamatergic contribution to the illness.

A vignette or exam stem tests this concept when it lists early candidate genes for schizophreniaA long-term mental illness involving episodes of psychosis such as hallucinations and delusions.Read more → (NRG1, DTNBP1, COMT, DISC1) and asks which relates specifically to glutamate signalling, or when it asks about the shift from candidate-gene to polygenic models of psychiatric genetics.

NRG1 and DTNBP1 both act through glutamatergic mechanisms, which distinguishes them from COMT (a dopamine-metabolising enzyme gene) and from DISC1 (disrupted-in-schizophreniaA long-term mental illness involving episodes of psychosis such as hallucinations and delusions.Read more → 1, first identified in a Scottish family with a chromosomal translocation) — mixing up which candidate gene points to which neurotransmitterA chemical messenger that nerve cells release to signal to the next cell.Read more → system is the commonest exam trap in this area.

A common trap is treating NRG1 or dysbindin as a confirmed single cause of schizophreniaA long-term mental illness involving episodes of psychosis such as hallucinations and delusions.Read more →; replication across different populations has been inconsistent, which is why they remain 'candidate' genes rather than established causes. A second trap is confusing NRG1's ErbB4/NMDA-receptor mechanism with dysbindin's vesicle-release mechanism — they act at different points in glutamatergic signalling. A third trap is forgetting that modern genome-wide association studies (GWAS) now attribute most schizophrenia risk to many common variants of small individual effect, not to any single candidate gene.

Step 1, identify whether the gene named acts on glutamate signalling (NRG1, DTNBP1) or a different system (COMT on dopamine, DISC1 on neurodevelopment). Step 2: recall that candidate-gene findings from this era had inconsistent replication. Step 3: if the question asks about current understanding, favour the polygenic, GWAS-based model over any single-gene explanation.