The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Abstract

Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders-for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene-environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research.

Figure 1

Summary of psychiatric genetic methods. (Adapted from Smoller et al, 2015.)

Figure 2

Complexity of causal relationships between genetic risk and environmental trauma/adversity. Only a subset of possible relationships are depicted. Genes (G) may (path a) influence PTSD directly or (b) by increasing the risk of index traumas (T_i) which in turn cause PTSD (c). In addition, index traumas may increase PTSD risk independent of genetic effects (d). In addition, trauma/adversity may act as risk exposures (R_e) that amplify risk (e and f) but are not a primary cause of PTSD. These risk exposures may themselves be under genetic influence (d). Finally, T_i and R_e may be correlated and each may modify the effect of risk genes (representing gene–environment interactions).

Figure 3

Cross-disorder genetic relationships for stress-related disorders. (a) Genetic correlations derived from twin studies. (Chantarujikapong et al, 2001; Hettema et al, 2006b; Sartor et al, 2012). (b) Common variant overlap derived from GWAS (numbers represent genetic correlations, PRS: polygene risk score) (Cross-Disorder Group of the Psychiatric Genomics Consortium et al, 2013; Nievergelt et al, 2015; Solovieff et al, 2014). (c) Example loci with effects reported across multiple disorders (Cross Disorder Group of the Psychiatric GWAS Consortium, 2013; Green et al, 2013). ADHD, attention deficit/hyperactivity disorder; AG, agoraphobia; BPD, bipolar disorder; GAD, generalized anxiety disorder; MDD, major depressive disorder; PD, panic disorder; PTSD, posttraumatic stress disorder; SAD, social anxiety disorder; SCZ, schizophrenia.