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

Autor:	Warren TL; UC Davis Center for Neuroscience., Tubbs JD; Department of Psychiatry, The University of Hong Kong.; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital.; Department of Psychiatry, Harvard Medical School., Lesh TA; UC Davis Imaging Research Center., Corona MB; UC Davis Center for Neuroscience., Pakzad S; UC Davis Imaging Research Center., Albuquerque M; UC Davis Imaging Research Center., Singh P; UC Davis Imaging Research Center., Zarubin V; UC Davis Imaging Research Center., Morse S; Washington University in St. Louis., Sham PC; Department of Psychiatry, The University of Hong Kong.; Centre for PanorOmic Sciences, The University of Hong Kong.; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong., Carter CS; UC Davis Imaging Research Center., Nord AS; UC Davis Center for Neuroscience.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Nov 15. Date of Electronic Publication: 2023 Nov 15.
DOI:	10.1101/2023.05.24.23290465
Abstrakt:	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 206 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. Competing Interests: Conflict of interest statement The authors declare no conflicts of interest or competing financial interests.
Databáze:	MEDLINE
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