Variation in the Williams syndrome GTF2I gene and anxiety proneness interactively affect prefrontal cortical response to aversive stimuli.
Characterizing the molecular mechanisms underlying the heritability of complex behavioral traits such as human anxiety remains a challenging endeavor for behavioral neuroscience. Copy-number variation (CNV) in the general transcription factor gene, GTF2I, located in the 7q11.23 chromosomal region that is hemideleted in Williams syndrome and duplicated in the 7q11.23 duplication syndrome (Dup7), is associated with gene-dose-dependent anxiety in mouse models and in both Williams syndrome and Dup7. Because of this recent preclinical and clinical identification of a genetic influence on anxiety, we examined whether sequence variation in GTF2I, specifically the single-nucleotide polymorphism rs2527367, interacts with trait and state anxiety to collectively impact neural response to anxiety-laden social stimuli. Two hundred and sixty healthy adults completed the Tridimensional Personality Questionnaire Harm Avoidance (HA) subscale, a trait measure of anxiety proneness, and underwent functional magnetic resonance imaging (fMRI) while matching aversive (fearful or angry) facial identity. We found an interaction between GTF2I allelic variations and HA that affects brain response: in individuals homozygous for the major allele, there was no correlation between HA and whole-brain response to aversive cues, whereas in heterozygotes and individuals homozygous for the minor allele, there was a positive correlation between HA sub-scores and a selective dorsolateral prefrontal cortex (DLPFC) responsivity during the processing of aversive stimuli. These results demonstrate that sequence variation in the GTF2I gene influences the relationship between trait anxiety and brain response to aversive social cues in healthy individuals, supporting a role for this neurogenetic mechanism in anxiety.
1] Section on Integrative Neuroimaging, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA [2] Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Jabbi
The Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
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Chen
1] Section on Integrative Neuroimaging, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA [2] Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Turner
1] Section on Integrative Neuroimaging, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA [2] Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Kohn
The Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
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White
1] Section on Integrative Neuroimaging, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA [2] Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Kippenhan
Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Dickinson
Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Kolachana
1] The Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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Mattay
1] The Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA [2] Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genomic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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Weinberger
1] Section on Integrative Neuroimaging, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA [2] Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
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Berman
D000293:Adolescent; D000328:Adult; D000786:Anger / Q000502:physiology; D001007:Anxiety / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D056915:DNA Copy Number Variations / Q000235:genetics*; D005239:Fear / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000503:physiopathology*; D019473:Transcription Factors, TFII / Q000235:genetics*; D018980:Williams Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
C104259:GTF2I protein, human; D019473:Transcription Factors, TFII