DEPRESSION AND ANXIETY 00:1–9 (2012) Research Article SEROTONIN TRANSPORTER LENGTH POLYMORPHISM, CHILDHOOD MALTREATMENT, AND CHRONIC DEPRESSION: A SPECIFIC GENE–ENVIRONMENT INTERACTION George W. Brown, Ph.D., 1∗ Maria Ban, Ph.D., 2 Thomas K. J. Craig, M.D., Ph.D., 1 Tirril O. Harris, D.H.C., 1 Joe Herbert, M.B., 3 and Rudolf Uher, M.D., Ph.D. 4,5 Background: Key questions about the interaction between the serotonin trans- porter length polymorphism (5-HTTLPR) and stress in the etiology of depres- sion remain unresolved. We test the hypotheses that the interaction is restricted to childhood maltreatment (as opposed to stressful events in adulthood), and leads to chronic depressive episodes (as opposed to any onset of depression), using gold-standard assessments of childhood maltreatment, severe life events, chronic depression, and new depressive onsets. Method: In a risk-enriched sample of 273 unrelated women, childhood maltreatment was retrospectively assessed with the Childhood Experience of Care and Abuse (CECA) interview and 5-HTTLPR was genotyped. A subset of 220 women was followed prospectively for 12 months with life events assessed with the Life Events and Difficulties (LEDS) interview. Any chronic episode of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were estab- lished with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview. Results: The short alleles of 5-HTTLPR moderated the relationship between childhood maltreatment and chronic depression in adulthood, reflected in a significant gene–environment interaction (RD = 0.226, 95% CI: 0.076– 0.376, P = .0032). 5-HTTLPR did not moderate the effects of either childhood maltreatment or severe life events on new depressive onsets. Conclusions: The short variant of the serotonin transporter gene specifically sensitizes to the effect of early-life experience of abuse or neglect on whether an adult depressive episode takes a chronic course. This interaction may be responsible for a substantial pro- portion of cases of chronic depression in the general population. Depression and Anxiety 00:1–9, 2012. C  2012 Wiley Periodicals, Inc. 1 Department of Health Service and Population Research, Insti- tute of Psychiatry, King’s College London, UK 2 Department of Neurology, Department of Clinical Neuro- sciences, University of Cambridge, Cambridge, UK 3 Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK 4 Department of Psychiatry, Dalhousie University, NS Canada 5 Social, Genetic, and Developmental Psychiatry Research Centre, King’s College London, UK Contract grant sponsor: The Medical Research Council, UK, and the Wellcome Trust funded the sample collection. INTRODUCTION Evidence for gene–environment interaction (G × E) involving the length polymorphism in the promoter of ∗ Correspondence to: George W. Brown, Health Service & Pop- ulation Research, Institute of Psychiatry, King’s College Lon- don, De Crespigny Park, London SE5 8AF, UK. E-mail: george. brown@kcl.ac.uk Received for publication 31 March 2012; Revised 20 June 2012; Accepted 25 June 2012 DOI 10.1002/da.21982 Published online in Wiley Online Library (wileyonlinelibrary.com). C  2012 Wiley Periodicals, Inc.