Common polymorphisms in dopamine-related genes combine to produce a 'schizophrenia-like' prefrontal hypoactivity.
Individual changes in dopamine-related genes influence prefrontal activity during cognitive-affective processes; however, the extent to which common genetic variations combine to influence prefrontal activity is unknown. We assessed catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) and dopamine D2 receptor (DRD2) G-T (rs2283265) single nucleotide polymorphisms and functional magnetic resonance imaging during an emotional response inhibition test in 43 healthy adults and 27 people with schizophrenia to determine the extent to which COMT Val108/158Met and DRD2 G-T polymorphisms combine to influence prefrontal response to cognitive-affective challenges. We found an increased number of cognitive-deficit risk alleles in these two dopamine-regulating genes predict reduced prefrontal activation during response inhibition in healthy adults, mimicking schizophrenia-like prefrontal hypoactivity. Our study provides evidence that functionally related genes can combine to produce a disease-like endophenotype.
1] School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Schizophrenia Research Lab, Neuroscience Research Australia, Sydney, NSW, Australia [3] Schizophrenia Research Institute, Darlinghurst, NSW, Australia [4] School of Psychology, Australian Catholic University, Strathfield, NSW, Australia.
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Vercammen
1] School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Schizophrenia Research Lab, Neuroscience Research Australia, Sydney, NSW, Australia [3] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Weickert
1] School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Schizophrenia Research Lab, Neuroscience Research Australia, Sydney, NSW, Australia [3] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Skilleter
1] School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Schizophrenia Research Lab, Neuroscience Research Australia, Sydney, NSW, Australia [3] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Lenroot
1] Schizophrenia Research Lab, Neuroscience Research Australia, Sydney, NSW, Australia [2] Schizophrenia Research Institute, Darlinghurst, NSW, Australia [3] School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
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Schofield
1] School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Schizophrenia Research Lab, Neuroscience Research Australia, Sydney, NSW, Australia [3] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Weickert
D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004644:Emotions / Q000502:physiology; D058068:Endophenotypes; D056344:Executive Function / Q000502:physiology; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000503:physiopathology*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*
D017448:Receptors, Dopamine D2; D002394:Catechol O-Methyltransferase