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The Journal of Neuroscience, February 14, 2007, 27(7):1584-1593; doi:10.1523/JNEUROSCI.5112-06.2007

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Behavioral/Systems/Cognitive
Allelic Variation in RGS4 Impacts Functional and Structural Connectivity in the Human Brain

Joshua W. Buckholtz,^1,2 Andreas Meyer-Lindenberg,^1,3,4 Robyn A. Honea,^1,2 Richard E. Straub,¹ Lukas Pezawas,¹ Michael F. Egan,¹ Radhakrishna Vakkalanka,¹ Bhaskar Kolachana,¹ Beth A. Verchinski,^1,3 Steven Sust,^1,2 Venkata S. Mattay,^1,3 Daniel R. Weinberger,¹ and Joseph H. Callicott^1,2

¹Clinical Brain Disorders Branch, ²Unit on Dynamic Imaging Genetics, ³Neuroimaging Core Facility, and ⁴Unit on Systems Neuroscience in Psychiatry, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1364

Correspondence should be addressed to Dr. Joseph H. Callicott, Building 10, Center Drive, Room 4C-216, MSC 1364, Bethesda, MD 20892-1364. Email: callicottj{at}mail.nih.gov

Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness.

Key words: G-protein; schizophrenia; genetics; fMRI; VBM; human

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Received June 26, 2006; revised Dec. 22, 2006; accepted Dec. 27, 2006.

Correspondence should be addressed to Dr. Joseph H. Callicott, Building 10, Center Drive, Room 4C-216, MSC 1364, Bethesda, MD 20892-1364. Email: callicottj{at}mail.nih.gov

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