The association of 5-HTTLPR genotype and depressive symptoms is moderated by physical activity Chad D. Rethorst a, * , Daniel M. Landers b , Craig T. Nagoshi c , Julianna T.D. Ross d a Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA b Department of Kinesiology, Arizona State University, USA c Department of Psychology, Arizona State University, USA d Translational Genomics Research Institute, Phoenix, AZ, USA article info Article history: Received 21 October 2009 Received in revised form 5 May 2010 Accepted 7 May 2010 Keywords: Depression Depressive symptoms Serotonin transporter gene Physical activity Exercise abstract The s allele serotonin transporter polymorphic region (5-HTTLPR) is associated with a number of physiological mechanisms that may increase the risk of elevated depressive symptoms. However, reports of a relationship between serotonin transporter polymorphic region (5-HTTLPR) genotype and depres- sive symptoms have thus far been inconclusive. This heterogeneity of results suggests that other factors may be moderating the relationship between 5-HTTLPR and depressive symptoms. Higher levels of physical activity are associated with lower levels of depressive symptoms. Mechanisms responsible for this association include alterations of the serotonergic system and the hypothalamicepituitary axis. The aim of the current study was to measure the moderating effect of physical activity on the relationship between 5-HTTLPR genotype and depressive symptoms. Participants, ages 18e23, provided a saliva sample for DNA analysis and completed questionnaires to assess depressive symptoms and physical activity. A hierarchical multiple regression analysis was conducted to examine the moderating effect of physical activity on the relationship between 5-HTTLPR genotype and depressive symptoms. Analysis revealed a significant interaction between 5-HTTLPR and physical activity (p ¼ .010). At low levels of physical activity, individuals with at least one s allele had significantly higher levels of depressive symptoms compared to ll individuals (p ¼ .011). This finding provides preliminary support for a moderating effect of physical activity on the relationship between 5-HTTLPR and depressive symptoms. Ó 2010 Elsevier Ltd. All rights reserved. In the United States, depression currently affects approximately 18.8 million American adults each year (National Institute of Mental Health, 2006). Along with the prevalence of depressive disorders, the cost to treat these disorders has grown. In 2000, the estimated costs associated with depressive disorders are $26 billion annually. Even in individuals that do not meet the diagnostic criteria for major depression, depressive symptoms have adverse effects. Elevated depressive symptoms are associated with an increased risk of major depression (Horwath et al., 1992) functional impair- ment (Lyness et al., 2007; Skodol et al., 1994; Judd and Paulus, 1996), higher rates of disability (Broadhead et al., 1990), and increased social dysfunction (Judd and Paulus, 1996; Judd et al., 1994). Due to the high monetary and health costs associated with elevated depressive symptoms, it is essential to identify factors that increase the risk of elevated depressive symptoms. Serotonin has been implicated in a number of processes in brain development and synaptic plasticity. Furthermore, dysfunction of the serotonergic system, including decreased 5-Hydroxyindole- acetic acid (5-HIAA), decreased free tryptophan, and decreased platelet 5-HT uptake sites, has been hypothesized as a mechanism for depressive disorders (Meltzer, 1989). The association between serotonergic function and depression is further strengthened by the fact that selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of many affective disorders (Goodnick and Goldstein, 1998). This evidence has led to the examination of the role of the genes that influence the serotonergic system, with most work focusing on the serotonin transporter polymorphic region. The serotonin transporter polymorphic region (5-HTTLPR) is char- acterized by two alleles: long (l) and short (s)(Lesch et al., 1996). Research has indicated a number of potential physiological mecha- nisms by which the 5-HTTLPR may ultimately facilitate the develop- ment of depressive symptoms (Owens and Nemeroff,1994). The s allele is associated with a lower transcription rate of serotonin transporter (5- HTT) (Lesch et al., 1996; Heils et al., 1996), lowered 5-HT 1A receptor * Corresponding author. Tel.: þ1 214 648 0153; fax: þ1 214 648 0167. E-mail address: chad.rethorst@utsouthwestern.edu (C.D. Rethorst). Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires 0022-3956/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2010.05.007 Journal of Psychiatric Research 45 (2011) 185e189