Abstract
“Schizotypy” is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [123I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.
Highlights
We investigated whether schizotypy is related to genetic variation within the DRD2 gene and whether they interact on a series of phenotypes implicated in schizophrenia
We found that DRD2 rs1076560 is associated with Schizotypal Personality Questionnaire (SPQ) scores in healthy subjects
We report an interaction between SPQ scores and the rs1076560 genotype on striatal IBZM binding
Summary
The risk for schizophrenia can be represented by a continuous Gaussian distribution in the general population (Plomin, 1999) with an arbitrary threshold to distinguish patients and healthy individuals (DSM-V diagnostic criteria) (Bhati, 2013). A corollary of this perspective is that individuals below the diagnostic threshold share some of the genetic risk for the disorder (Plomin, 1999). Higher rates of schizotypal traits have been found in first-degree relatives of patients with schizophrenia compared with healthy subjects, suggesting that schizotypy is related to a genetic risk for the disorder (Kety et al, 1994; Kendler et al, 1995; Tsuang et al, 1999; Vollema et al, 2002; Ettinger et al, 2014). Variable schizotypy has been found in nonpsychiatric individuals (Chen et al, 1997; Croft et al, 2001; Fonseca-Pedrero et al, 2007, 2008, 2009, 2011; Aguirre et al, 2008; Kwapil et al, 2008; Noguchi et al, 2008; Wilson et al, 2008; Bedwell et al, 2009), suggesting that this trait may be studied in healthy subjects without the confounds and limitations commonly found in patients
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