Allelic variation in RGS4 impacts functional and structural connectivity in the human brain.
Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G alpha-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.
Buckholtz
Joshua W
JW
Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1364, USA.
Meyer-Lindenberg
Andreas
A
Honea
Robyn A
RA
Straub
Richard E
RE
Pezawas
Lukas
L
Egan
Michael F
MF
Vakkalanka
Radhakrishna
R
Kolachana
Bhaskar
B
Verchinski
Beth A
BA
Sust
Steven
S
Mattay
Venkata S
VS
Weinberger
Daniel R
DR
Callicott
Joseph H
JH
D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000098:blood supply* / Q000502:physiology*; D001931:Brain Mapping; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics*
D020710:RGS Proteins; C098799:RGS4 protein; D010100:Oxygen