A review of Kohrt et al.: Cross-Cultural Gene−Environment Interactions in Depression, PTSD, and the Cortisol Awakening Response

by Jake Aronoff

​            In this study, Kohrt et al. (2015) examined gene-environment interactions in relation to phenotypic expressions of depression and PTSD as well as a biological marker in the form of cortisol awakening responses. This study is unique in that it examines a specific gene-environment interaction in an unconventional setting: Nepal. The authors note that while there has been increased attention in global mental health, studies have focused mostly on populations in high income countries and of European descent. Thus, the authors intended to examine whether previously reported relations between specific genetic profiles, childhood maltreatment, and adult expressions of depression and PTSD were also present in a population outside of a high income country and not of European descent.
 
            The gene of interest to the researchers was FKBP5. Previous studies have examined alleles of this gene, and found interactions with child abuse and later life risk for depression as well as PTSD. Thus, the researchers wanted to see if this interaction could also be observed in a population conventionally not studied. Along with examining depression and PTSD, they also measured cortisol awakening responses. Cortisol awakening responses were measured because of the role FKBP5 has in the stress response as well as the fact that depression and PTSD are stress-related. The stress response relies on the hypothalamic-pituitary-adrenal (HPA) axis, and its functioning can be altered by FKBP5. Certain alleles of FKBP5 can do this by enhancing the gene’s expression. This results in a decreased efficiency of negative HPA feedback (the brain knowing when to turn off the stress response), which prolongs HPA activation after exposure to a stressor. Cortisol, a steroid hormone, is the end product of the HPA axis, being produced by the adrenal gland. Thus, the cortisol awakening responses served as biological markers for the functioning of the HPA axis that can be altered by different alleles of FKBP5.
           
            The researchers found an interaction of a specific genotype with childhood maltreatment and depression, but not PTSD. The genotype found to have the highest risk for developing PTSD in the presence of child abuse in a previous study was associated with the most severe depressive symptoms. Also observed in individuals with this genotype were opposite cortisol awakening responses depending on presence of childhood maltreatment. For individuals with this genotype who experienced childhood maltreatment, their cortisol levels dropped from the time of waking to thirty minutes later, whereas the opposite occurred in individuals with this same genotype who did not experience childhood maltreatment. For these individuals, cortisol levels rose from the time of waking to thirty minutes later. The researchers posit that individuals with this genotype may be more sensitive to early environmental conditions, and are more likely to experience epigenetic changes in the expression of FKBP5 (a genetic-epigenetic interaction) that alters the functioning of the HPA, an alteration that persists into adulthood. Thus, the researchers entertain the possibility that individuals with this particular genotype who experienced prolonged childhood maltreatment, and therefore prolonged elevations of cortisol, have negative cortisol awakening responses and hypocortisolism (low cortisol levels) as adults.
 
            The potential explanation proposed for why this study replicated previous findings on the interaction of genotype, childhood maltreatment, and depression but not PTSD was the cultural meaning associated with depression and PTSD in different parts of the world. In American and European populations, PTSD is less stigmatized than depression. However, in South Asia, where this study took place, PTSD is more stigmatized than depression. Thus, due to cultural differences regarding PTSD, there might have been under-reporting. The researchers also rely on the cultural context to explain why cortisol awakening responses had the most statistically significant gene-environment interaction effect. However, while cultural variation may influence self-reports of mental health, it must also be noted that measures of cortisol are not always perfect indicators of mental health. For example, approximately half of individuals with major depression have elevated cortisol levels (Sapolsky 2004). Therefore, there is not a single cortisol profile for depression, and this may be part of the explanation for why cortisol awakening responses had a more statistically significant gene-environment interaction effect than depression in this study.
 
            The researchers note some limitations as well as implications of their study. They note that the small number of individuals with the genotype that they observed such a strong gene-environment interaction with limits generalizability of their findings. They also note that individuals with this particular genotype who also experienced childhood maltreatment reported waking times approximately thirty minutes later than other participants. Therefore, they suggest further study on cortisol awakening response differences and different wake times. One implication of the study the researchers note is the importance of culturally and contextually diverse samples in order to avoid gene-environment associations being generalized based on samples of populations in high income countries of European descent. Another important implication the researchers note is the prevention of childhood maltreatment, as even in this setting of high exposure to political violence child abuse still had a significant effect on adult mental health and HPA regulation.
 
References:
 
Kohrt, Brandon A., Carol M. Worthman, Kerry J. Ressler, Kristina B. Mercer, Nawaraj Upadhaya, Suraj Koirala, Mahendra K. Nepal, Vidya Dev Sharma, and Elisabeth B. Binder. "Cross-cultural gene− environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia: GxE interactions in South Asia." International Review of Psychiatry 27, no. 3 (2015): 180-196.
 
Sapolsky, Robert M. Why zebras don't get ulcers: The acclaimed guide to stress, stress-related diseases, and coping-now revised and updated. Macmillan, 2004.