Cross-cultural gene− environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia

Abstract

Despite increased attention to global mental health, psychiatric genetic research has been dominated by studies in high-income countries, especially with populations of European descent. The objective of this study was to assess single nucleotide polymorphisms (SNPs) in the FKBP5 gene in a population living in South Asia. Among adults in Nepal, depression was assessed with the Beck Depression Inventory (BDI), post-traumatic stress disorder (PTSD) with the PTSD Checklist-Civilian Version (PCL-C), and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). FKBP5 SNPs were genotyped for 682 participants. Cortisol awakening response (CAR) was assessed in a subsample of 118 participants over 3 days. The FKBP5 tag-SNP rs9296158 showed a main effect on depressive symptoms (p = 0.03). Interaction of rs9296158 and childhood maltreatment predicted adult depressive symptoms (p = 0.02) but not PTSD. Childhood maltreatment associated with endocrine response in individuals homozygous for the A allele, demonstrated by a negative CAR and overall hypocortisolaemia in the rs9296158 AA genotype and childhood maltreatment group (p < 0.001). This study replicated findings related to FKBP5 and depression but not PTSD. Gene–environment studies should take differences in prevalence and cultural significance of phenotypes and exposures into account when interpreting cross-cultural findings.

Acknowledgements

The authors thank the community of Jumla, District Health Officer Badrai Chapagain, and research assistants Renu Shrestha, Krishna Maya Neupane, and Makunda Chapagain, as well as the assistance of Ganesh Rokaya and 4S Nepal. Thanks to Daniel Hruschka for his helpful suggestions on the manuscript and analyses. Thanks to Anvita Bhardwaj for assistance revising the manuscript.

Declaration of interest: Brandon Kohrt was supported by National Institute of Mental Health (NIMH) National Research Service Award (NRSA) F31 MH075584, Wenner-Gren Foundation for Anthropological Research Dissertation Research Award, and the Graduate School of Arts and Sciences, Emory University, Atlanta, Georgia. Carol Worthman received support from the Global Health Institute, Emory University, Atlanta, Georgia. Kerry Ressler was supported by the NIMH, (MH071537) and Burroughs Wellcome Foundation. At the time of the study, Elisabeth Binder was supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award, a Clinical Investigator award from Pfizer Pharma- ceuticals, the Doris Duke charitable foundation and NIMH (MH071537; MH076024; MH077083). She is co-inventor on the following patent applications: ‘FKBP5: a novel target for antidepressant therapy’, International publication number: WO 2005/054500 and ‘Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments’, International application number: PCT/EP2005/005194.

Author contributions: B.A.K. designed, supervised, and implemented the epidemiological study, performed the statistical analyses, and drafted the manuscript. C.M.W. supervised the study design, cortisol analyses, and revised the manuscript. K.J.R., K.B.M., and E.B.B. supervised the genetic study, genetic analyses, and revised the manuscript. N.U., S.K., V.D.S., and M.K.N. contributed to the study design, implementation, and supervision in Nepal. All authors approved the manuscript. The authors alone are responsible for the content and writing of the paper.