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A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, 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 PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

Theories of psychotic illness suggest that abnormal intrinsic functional connectivity may explain its characteristic positive and disorganization symptoms as well as lead to impaired general functioning. Here we used resting state functional magnetic resonance imaging (fMRI) to evaluate associations between these symptoms and the degree to which global connectivity is abnormal in early psychosis (EP). Eighty-six healthy controls (HCs) and 108 individuals with EP with resting state fMRI data were included in primary analyses. The EP group included 83 participants with schizophrenia-spectrum disorders and 25 with bipolar disorder type I with psychotic features. A global intrinsic connectivity "similarity index" for each EP individual was determined by calculating its correlation with the average HC connectivity matrix extracted using Schaefer atlases of multiple parcellations (100, 200, 300, and 400 region parcellations). As hypothesized, connectivity similarity with the average HC matrix was negatively associated with Brief Psychiatric Rating Scale total score, Scale for the Assessment of Positive Symptoms total score, and disorganization symptoms. Similarity was also positively associated with Global Assessment of Functioning score. Results were not driven by sex or diagnosis effects and were consistent across parcellation schemes. These results support the hypothesis that changes in whole-brain connectivity patterns are associated with psychosis symptoms and support the use of functional connectivity as a biomarker for these symptoms in EP.