Neurotransmitter-specific polygenic scores dissect clinical heterogeneity in schizophrenia

Pathway-stratified polygenic scores across acetylcholine, dopamine, GABA, glutamate, and serotonin define five schizophrenia patient profiles, including Ach and Glu groups linked to distinct symptom severity and onset.

• Why it matters: Global polygenic scores explain limited clinical variability in schizophrenia, leaving heterogeneity poorly captured for symptom dimensions and longitudinal outcomes.
• What they did: Common variants were annotated to five neurotransmitter pathways and used to compute sex- and ancestry-adjusted sPGS in two cohorts (N=3,044 and N=645), then top-decile clustering formed five mutually exclusive profiles.
• The result: gPGS showed no significant clinical associations, while Ach and Glu profiles mapped to clinically relevant differences: Ach had higher overall PANSS severity, and Glu showed more severe negative symptoms, earlier AAO, reduced three-year remission, and poorer treatment response; GABA risk related to three-year remission.

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