Genetic influences on the neural and physiological bases of acute threat: A research domain criteria (RDoC) perspective

Abstract

The NIMH Research Domain Criteria (RDoC) initiative aims to describe key dimensional constructs underlying mental function across multiple units of analysis—from genes to observable behaviors—in order to better understand psychopathology. The acute threat (“fear”) construct of the RDoC Negative Valence System has been studied extensively from a translational perspective, and is highly pertinent to numerous psychiatric conditions, including anxiety and trauma-related disorders. We examined genetic contributions to the construct of acute threat at two units of analysis within the RDoC framework: 1) neural circuits and 2) physiology. Specifically, we focused on genetic influences on activation patterns of frontolimbic neural circuitry and on startle, skin conductance, and heart rate responses. Research on the heritability of activation in threat-related frontolimbic neural circuitry is lacking, but physiological indicators of acute threat have been found to be moderately heritable (35-50%). Genetic studies of the neural circuitry and physiology of acute threat have almost exclusively relied on the candidate gene method and, as in the broader psychiatric genetics literature, most findings have failed to replicate. The most robust support has been demonstrated for associations between variation in the serotonin transporter (SLC6A4) and catechol-O-methyltransferase (COMT) genes with threat-related neural activation and physiological responses. However, unbiased genome-wide approaches using very large samples are needed for gene discovery, and these can be accomplished with collaborative consortium-based research efforts, such as those of the Psychiatric Genomics Consortium (PGC) and Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium.

The genetics of anxiety‐related negative valence system traits

“…Numerous human candidate gene association studies have been conducted in this area since the original Hariri et.al study, many of which are described in a recent review focusing specifically on the genetics of NVS acute threat systems [Sumner et al, ] and prior reviews by Scharinger et al [] and Savitz and Drevets []. We briefly summarize those findings and discuss a few studies not previously covered.…”

“…The amygdala is a small, bilateral structure in the temporal lobe that plays a major role in fear and emotional memory [Domschke and Dannlowski, ; Scharinger et al, ]. Amygdala reactivity, or the magnitude of response of the amygdala to a stimulus, is typically assessed with a functional magnetic resonance imaging (fMRI) task in which participants are shown pictures of emotional faces (expressing threat‐relevant emotions of fear or anger) or non‐facial affect‐arousing imagery, and the hemodynamic response in the amygdala is measured [Domschke and Dannlowski, ; Sumner et al, ]. Following an early report by Hariri et al [] that the 5‐HTTLPR functional polymorphism was associated with amygdala reactivity to fear‐relevant stimuli, there has been an abundance of genetic association studies investigating the role of 5‐HTTPLR and other candidate genetic variants in amygdala reactivity.…”

“…A variety of other candidate genes have been investigated for their role in amygdala reactivity in the past few years, although most still require replication. Sumner et al [] and Savits and Drevits [2009] review evidence of association for the BDNF Val66Met polymorphism, with the evidence pointing to greater reactivity in carriers of the Met allele. In other individual studies of genes putatively associated with internalizing disorders, variants in the androgen receptor ( AR ; trinucleotide repeat), acid‐sensing ion channel 1 ( ASIC1/ACCN2 ; rs10875995), fatty acid amide hydrolase ( FAAH ; rs324420), FK506 binding protein 5 ( FKBP5 ; rs1360780), neuropeptide Y ( NPY ; rs16147), mineralocorticoid receptor ( NR3C2 ; rs5522), and monoaminergic transmission‐related PCLO (rs2522833) genes were significantly associated with amygdala reactivity to emotional faces [Hariri et al, ; Domschke et al, ; Manuck et al, ; Bogdan et al, ; White et al, ; Woudstra et al, ; Smoller et al, ; Holz et al, ].…”

Conceptualization of PTSD from the Vietnam War to Current Conflicts and Beyond

“…Nevertheless, one development related to PTSD nosology is the Research Domain Criteria (RDoC) initiative. This approach aims to depict dimensional constructs underlying mental function across multiple constructs to understand the psychopathology of mental disorders (Sumner, Powers, Jovanovic & Koenen, 2015). Examination of the genetic contributions of acute threat reactions related to neural circuits and mammalian physiology seems promising for future PTSD investigations (Sumner et al, 2015).…”

“…This approach aims to depict dimensional constructs underlying mental function across multiple constructs to understand the psychopathology of mental disorders (Sumner, Powers, Jovanovic & Koenen, 2015). Examination of the genetic contributions of acute threat reactions related to neural circuits and mammalian physiology seems promising for future PTSD investigations (Sumner et al, 2015). In the past, genetic studies of the neural circuitry and physiology of acute threat reactions have typically used candidate gene methods, but these techniques have had only limited success.…”