1. Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo.
- Author
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Sportelli L, Eisenberg DP, Passiatore R, D'Ambrosio E, Antonucci LA, Bettina JS, Chen Q, Goldman AL, Gregory MD, Griffiths K, Hyde TM, Kleinman JE, Pardiñas AF, Parihar M, Popolizio T, Rampino A, Shin JH, Veronese M, Ulrich WS, Zink CF, Bertolino A, Howes OD, Berman KF, Weinberger DR, and Pergola G
- Subjects
- Humans, Male, Female, Adult, Caudate Nucleus metabolism, Signal Transduction, Middle Aged, Hippocampus metabolism, Multifactorial Inheritance, Genetic Predisposition to Disease, Dorsolateral Prefrontal Cortex metabolism, Reward, Dopamine metabolism, Dopamine biosynthesis, Schizophrenia genetics, Schizophrenia metabolism, Corpus Striatum metabolism
- Abstract
The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia., (© 2024. The Author(s).)
- Published
- 2024
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