Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

Merging genetic risk, neurological phenotypes, and clinical presentation is a primary goal for psychiatry. Pursuing this goal, we tested association between phenotypes and overall and pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 206 demographically diverse cases with a psychotic disorder and 115 matched controls with comprehensive psychiatric and neurological phenotyping. DNA was extracted from blood and genotyped. We calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To dissect convergent mechanisms of symptoms, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ and BP PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were significantly associated with specific symptoms; most notably, increased glutamatergic pPGS was associated with deficits in cognitive control and altered cortical activation during cognitive control task-based fMRI. Finally, unbiased symptom-driven clustering identified three diagnostically mixed case groups with distinct symptom profiles that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. These clusters had specific genetic risk profiles and differential response to treatment, and outperformed diagnosis in predicting glutamate and GABA pPGS. Our findings suggest pathway-based PGS analysis may be a powerful path forward for identifying convergent mechanisms driving psychotic disorders and linking genetic risk with endophenotypes.