The DRD1-by-Urbanicity and DRD2-by-Urbanicity effect on working memory investigated by BOLD fMRI

Authors

• M Grunnagle
• JL Ihne
• S Marenco
• DR Weinberger
• KF Berman
• JH Callicott

Abstract

Background: Working memory deficits are a hallmark intermediate phenotype in schizophrenia. A gene-by-environment interaction between Catechol-O-methyltransferase (COMT) and childhood urban living, or urbanicity, was reflected in prefrontal activation during working memory. Given the crucial role of the dopaminergic pathway in optimal cognitive function involving PFC, it is necessary to investigate other aspects of the dopamine system, specifically the dopamine 1 (DRD1) and 2 (DRD2) receptors. The minor, G allele in the single-nucleotide polymorphism (SNP) rs11749676 of DRD1, has been correlated with increased risk for schizophrenia compared to the major, A allele. The T allele of DRD2, rs1076560, results in a decreased ratio of D2 short (D2S) to D2 long (D2L) isoforms correlating to greater PF activity, or decreased efficiency, compared to the G allele. Methods: In an ongoing study recruiting healthy volunteers, ages 18-54, DRD1-by-urbanicity (n=103) and DRD2-by-urbanicity (n=149) interactions were investigated using BOLD fMRI activation data collected during the N-back working memory task. Multiple regression analysis was done using SPM8. Results: DRD1-by-urbanicity interaction correlated with greater activation in Brodmann Areas 8 and 9 with increasing risk factors, i.e. G allele polymorphism and a more urban childhood environment. DRD2-by-urbanicity interaction analysis showed greater activation in Brodmann Area 10 for lower risk populations, while higher risk populations showed greater activation in the insula, thalamus, and substania nigra. Conclusion: These results suggest that other genes in the dopamine system besides COMT may contribute to modulation of risk for schizophrenia by urban upbringing.

Scientific Focus Area: Neuroscience

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