1. Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis
- Author
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Warren, Tracy L, Tubbs, Justin D, Lesh, Tyler A, Corona, Mylena B, Pakzad, Sarvenaz S, Albuquerque, Marina D, Singh, Praveena, Zarubin, Vanessa, Morse, Sarah J, Sham, Pak Chung, Carter, Cameron S, and Nord, Alex S
- Subjects
Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Serious Mental Illness ,Human Genome ,Neurosciences ,Schizophrenia ,Mental Illness ,Clinical Research ,Genetics ,Mental Health ,Behavioral and Social Science ,Bipolar Disorder ,Brain Disorders ,Prevention ,2.1 Biological and endogenous factors ,Mental health ,Good Health and Well Being ,Humans ,Female ,Male ,Multifactorial Inheritance ,Psychotic Disorders ,Adult ,Neurotransmitter Agents ,Genome-Wide Association Study ,Genetic Predisposition to Disease ,Endophenotypes ,Glutamic Acid ,Dopamine ,Case-Control Studies ,Young Adult ,Genotype ,Magnetic Resonance Imaging ,Risk Factors ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - Abstract
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.
- Published
- 2024