title: 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.
authors.affiliation: Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, New York.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sumner
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Abigail
authors.initials: A
authors.lastname: Powers
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovanovic
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.|Psychiatric and Neurodevelopmental Genetics Unit and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.|The Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Karestan C
authors.initials: KC
authors.lastname: Koenen
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics* / Q000503:physiopathology*; D055106:Genome-Wide Association Study; D006801:Humans; D009315:National Institute of Mental Health (U.S.); D009434:Neural Pathways / Q000502:physiology; D012106:Research; D014481:United States
keywords: RDoC; acute threat; genetics; neural circuit; physiology