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

内表型 精神病 精神分裂症(面向对象编程) 全基因组关联研究 神经递质 心理学 精神科 多巴胺 谷氨酸受体 双相情感障碍 遗传关联 神经科学 医学 认知 内科学 单核苷酸多态性 遗传学 生物 中枢神经系统 基因型 基因 受体
作者
Tracy Warren,Justin D. Tubbs,Tyler A. Lesh,Mylena B. Corona,Sarvenaz Pakzad,Marina Albuquerque,Praveena Singh,Vanessa C. Zarubin,Sarah Morse,Pak C. Sham,Cameron S. Carter,Alex S. Nord
出处
期刊:Cold Spring Harbor Laboratory - medRxiv 被引量:1
标识
DOI:10.1101/2023.05.24.23290465
摘要

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 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.
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