Genetic Influences on the Neural and Physiological Bases of Acute Threat: A Research Domain Criteria (RDoC) Perspective

• Type of Material: Article
• Authors: Jennifer A. Sumner, Columbia University; Abigail Powers Lott, Emory University; Tanja Jovanovic, Emory University; Karenstan C. Koenen, Harvard University
• Language: English
• Date: 2016-01-01
• Publisher: Wiley-Blackwell
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/ajmg.b.32384
• Title of Journal or Parent Work: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
• Volume: 171
• Issue: 1
• Start Page: 44
• End Page: 64
• Grant/Funding Information: Funding: R21 MH098212
• Keywords: PANIC DISORDER; GENOME-WIDE ASSOCIATION; BDNF VAL66MET POLYMORPHISM; ACOUSTIC STARTLE; physiology; genetics; CATECHOL-O-METHYLTRANSFERASE; RDoC; neural circuit; Psychiatry; SEROTONIN TRANSPORTER GENE; FEAR-POTENTIATED STARTLE; Genetics & Heredity; EARLY-LIFE STRESS; TRYPTOPHAN-HYDROXYLASE ISOFORM; Life Sciences & Biomedicine; POSTTRAUMATIC-STRESS-DISORDER; Science & Technology; acute threat
• Research Categories: Biology, Genetics; Psychology, Behavioral; Health Sciences, Epidemiology

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.