INTERACTION OF CHRONIC STRESS WITH SEROTONIN TRANSPORTER AND CATECHOL-O-METHYLTRANSFERASE POLYMORPHISMS IN PREDICTING YOUTH DEPRESSION

Background: Investigations of gene environment interaction (G x E) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress depression relationship. However, recent evidence for 5-HTTLPR G x E in depression has been inconsistent. This study examined the moderating effect of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene on the strength of 5-HTTLPR G x E. Methods: A community sample of youth (n = 384) was genotyped for 5-HTTLPR and COMT. A multi-method, multi-informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. G x G x E was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Results: Significant three-way interactions were observed for both depressive symptoms and diagnoses, such that 5-HTTLPR G x E occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5-HTTLPR LL genotype exerted a protective effect in the face of stress. No genetic main effect or two-way G x E was found for 5-HTTLPR. Conclusions: Inconsistent 5-HTTLPR G x E findings to date may be partly attributable to unmeasured epistatic effects between 5-HTTLPR and COMT val158met. Identifying the conditions under which 5-HTTLPR G x E is most likely to operate may allow depression prevention and treatment efforts to target youth at highest risk. Depression and Anxiety 27:737-745, 2010. (C) 2010 Wiley-Liss, Inc.