期刊
MOLECULAR PSYCHIATRY
卷 28, 期 5, 页码 1995-2006出版社
SPRINGERNATURE
DOI: 10.1038/s41380-021-01108-y
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Dopaminergic dysfunction is associated with genetic risk for psychosis, particularly in individuals with 22q11.2 deletion. This study found increased striatal dopamine synthesis capacity in individuals with 22q11.2 deletion compared to healthy controls and individuals with 22q11.2 duplication. Furthermore, dopamine synthesis was positively correlated with the severity of psychosis-risk symptoms.
Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Ki(cer). There was an inverse linear effect of copy number variant number on striatal Ki(cer) value (B = -1.2 x 10(-3), SE = 2 x 10(-4), p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki(cer) was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen's d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen's d = 2) groups. Moreover, Ki(cer) was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers.
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