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Influence of RGS2 on Anxiety-Related Temperament, Personality, and Brain Function
Jordan W. Smoller, MD, ScD;
Martin P. Paulus, MD;
Jesen A. Fagerness, BA;
Shaun Purcell, PhD;
Lesley H. Yamaki, BS;
Dina Hirshfeld-Becker, PhD;
Joseph Biederman, MD;
Jerrold F. Rosenbaum, MD;
Joel Gelernter, MD;
Murray B. Stein, MD, MPH
Arch Gen Psychiatry. 2008;65(3):298-308.
Context Although anxiety disorders are heritable, their genetic and phenotypic complexity has made the identification of susceptibility genes difficult. Well-validated animal models and intermediate phenotypes provide crucial tools for genetic dissection of anxiety. The gene encoding regulator of G protein signaling 2 (Rgs2) is a quantitative trait gene that influences mouse anxiety behavior, making its human ortholog (RGS2) a compelling candidate gene for human anxiety phenotypes.
Objective To examine whether variation in RGS2 is associated with intermediate phenotypes for human anxiety disorders.
Design Family-based and case-control association analysis of single-nucleotide polymorphisms at the RGS2 locus in 3 independent samples.
Setting Massachusetts General Hospital, University of California, San Diego, and San Diego State University.
Participants Study participants included a family-based sample (n = 119 families) of children who underwent laboratory-based assessments of temperament (behavioral inhibition), a sample of 744 unrelated adults who completed assessments of extraversion and introversion, and 55 unrelated adults who underwent functional magnetic resonance imaging measures of response to emotional faces.
Main Outcome Measures Laboratory-based behavioral measures of childhood temperament, self-report measure of personality, and functional magnetic resonance imaging response to emotion processing.
Results Markers spanning RGS2 were associated with childhood behavioral inhibition, a temperamental precursor of social anxiety disorder (haplotype P = 3 x 10–5; odds ratio, 2.99 in complete trios). In independent samples, RGS2 markers, including rs4606, which has previously been associated with RGS2 expression, were also associated with introversion (a core personality trait in social anxiety disorder) and with increased limbic activation (insular cortex and amygdala) during emotion processing (brain phenotypes correlated with social anxiety). The genotype at rs4606 explained 10% to 15% of the variance in amygdala and insular cortex activation to emotional faces.
Conclusions These results provide the first evidence that a gene that influences anxiety in mice is associated with intermediate phenotypes for human anxiety disorders across multiple levels of assessment, including childhood temperament, adult personality, and brain function. This translational research suggests that some genetic influences on anxiety are evolutionarily conserved and that pharmacologic modulation of RGS2 function may provide a novel therapeutic approach for anxiety disorders.
Author Affiliations: Psychiatric Genetics Program in Mood and Anxiety Disorders (Dr Smoller and Ms Yamaki), Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (Drs Smoller and Purcell, Mr Fagerness, and Ms Yamaki), and Department of Psychiatry (Drs Smoller, Purcell, Hirshfeld-Becker, Biederman, and Rosenbaum, Mr Fagerness, and Ms Yamaki), Massachusetts General Hospital, Harvard Medical School, Boston; Departments of Psychiatry (Drs Paulus and Stein) and Family and Preventive Medicine (Dr Stein), University of California, San Diego, and VA San Diego Healthcare System; and Departments of Psychiatry, Genetics, and Neurobiology, Division of Human Genetics in Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Dr Gelernter).
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