Imaging genomics applied to anxiety, stress response, and resiliency

Anxiety and stress response/resiliency are heritable traits central to the etiology of multiple psychiatric diseases, but efforts to identify genetic variation influencing this broad domain of neurobiological function are hampered by the coarseness of the phenotypic measures and the effects of environmental factors. Neuroimaging offers a powerful approach for assessing functional neuronal activity. Neurophysiological measures can serve as intermediate phenotypes more directly linked to small gene effects, compared with behavioral end points of neural dysfunction. Imaging genomics is a relatively new research area that is concerned with linking functional gene variants and brain information processing. Here, we will focus on processes affected by anxiety and stress. Neuroimaging has been combined with genetic analysis to reveal genetic effects of functional variants of the serotonin transporter (5-HTT) and catechol-O-methyltransferase (COMT) genes on brain response to stressful stimuli. The low-expressing allele of the 5-HTT promoter polymorphism (HTTLPR) is associated with anxiety and with greater amygdala and other regional responses to emotional. The COMT Met158 allele leads to lower COMT activity and has also been associated with anxiety, and the effect of this gene is apparently additive with HTTLPR. Individuals with Met158 genotypes are more sensitive to pain stress and, as shown by C¹¹ Carfentanil imaging, have diminished ability to upregulate opioid release after pain/stress. These results suggest that functional variants of 5-HTT and COMT impact brain functions involved in stress and anxiety.