Risk and resilience: genetic and environmental influences on development of the stress response

Depress Anxiety. 2009;26(11):984-92. doi: 10.1002/da.20605.


Exposure to stressful events during development has consistently been shown to produce long-lasting alterations in the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood and anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by genexenvironment interactions involving polymorphisms within two key genes, CRHR1 and FKBP5. Data suggest that these genes regulate HPA axis function in conjunction with exposure to child maltreatment or abuse. In addition, a large and growing body of preclinical research suggests that increased activity of the amygdala-HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress-related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning, which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Amygdala / physiopathology
  • Anxiety Disorders / genetics*
  • Anxiety Disorders / physiopathology
  • Anxiety Disorders / psychology
  • Arousal / genetics*
  • Arousal / physiology
  • Child
  • Child Abuse / psychology
  • Emotions / physiology
  • Genetic Predisposition to Disease / genetics*
  • Genetic Predisposition to Disease / psychology
  • Humans
  • Hypothalamo-Hypophyseal System / physiopathology
  • Life Change Events*
  • Mood Disorders / genetics*
  • Mood Disorders / physiopathology
  • Mood Disorders / psychology
  • Nerve Net / physiopathology
  • Pituitary-Adrenal System / physiopathology
  • Polymorphism, Genetic / genetics
  • Receptors, Corticotropin-Releasing Hormone / genetics*
  • Resilience, Psychological*
  • Social Environment*
  • Socioeconomic Factors
  • Stress Disorders, Post-Traumatic / genetics*
  • Stress Disorders, Post-Traumatic / physiopathology
  • Stress Disorders, Post-Traumatic / psychology
  • Tacrolimus Binding Proteins / genetics*


  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 5