ORIGINAL ARTICLE The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: a meta-analysis R Miller, M Wankerl, T Stalder, C Kirschbaum and N Alexander Recent meta-analyses have stimulated an active debate on whether the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with an elevated vulnerability to psychiatric diseases upon exposure to environmental adversity. As a potential mechanism explaining genotype-dependent differences in stress sensitivity, altered stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis has been investigated in several experimental studies, with most of these studies comprising small samples. We evaluated the association of 5-HTTLPR genotype and cortisol reactivity to acute psychosocial stress by applying a meta-analytical technique based on eleven relevant data sets (total N ¼ 1686), which were identified through a systematic literature search up to October 2011. This meta-analysis indicates a small (d ¼ 0.27), but significant association between 5-HTTLPR genotype and HPA-axis reactivity to acute psychosocial stress with homozygous carriers of the S allele displaying increased cortisol reactivity compared with individuals with the S/L and L/L genotype. The latter association was not further moderated by participants’ age, sex or the type of stressor. Formal testing revealed no evidence for a substantial selection or publication bias. Our meta-analytical results are consistent with a wide variety of experimental studies indicating a significant association between 5-HTTLPR genotype and intermediate phenotypes related to stress sensitivity. Future studies are needed to clarify the consistency of this effect and to further explore whether altered HPA-axis stress reactivity reflects a potential biological mechanism conveying an elevated risk for the development of stress-related disorders in S allele carriers. Molecular Psychiatry (2012) 0, 000–000. doi:10.1038/mp.2012.124 Keywords: cortisol; 5-HTTLPR; hypothalamus-pituitary-adrenal axis; meta-analysis; saliva; stress INTRODUCTION During the past years, a substantial amount of studies have been conducted on gene–environment (G  E) interaction effects in the context of stress-related psychiatric disorders. Of the many candidate gene variants studied, a prominent example has been a prospective longitudinal study by Caspi et al., 1 indicating genetic variation in the promoter region (5-HTTLPR) of the serotonin transporter gene to moderate the association between life stress and depression. This 43 bp insertion/deletion polymorphism presumably influences the transcription rate of the serotonin transporter (5-HTT) gene with the short (S) allele being transcriptionally less efficient than the long (L) allele, 2,3 even though recent studies suggest a more complex mechanism to mediate long-term effects of 5-HTTLPR on serotonergic neurotransmission. 4,5 Regardless of the precise molecular mechanism, accumulating evidence suggests an increased vulnerability to depression in carriers of at least one S allele with a significant history of aversive life events. 6,7 Recent meta-analyses stimulated an active debate regarding the latter association, by either supporting 8 or providing no evidence 9,10 for significant G  E interaction. As a consequence of this ongoing controversy, experimental studies addressing bio- logical quantitative traits underlying elevated stress sensitivity in S allele carriers become increasingly important. 11 In particular, altered stress-induced activation of the hypothalamus-pituitary- adrenal (HPA) axis has been discussed as a potential inter- mediate phenotype (or ‘endophenotype’), possibly conveying an increased risk for depression as a function of 5-HTTLPR genotype. 12,13 Consequently, several experimental studies have investigated the association between 5-HTTLPR genotype and HPA-axis reactivity to standardized laboratory stressors in healthy indivi- duals. 14–22 The biological rationale for these association studies derives from an extensive literature documenting the important role of serotonergic neurotransmission in HPA axis regulation. 23,24 As a result of the above-mentioned studies, individuals carrying two copies of the S allele have been repeatedly shown to exhibit elevated cortisol secretion in response to acute psychosocial stress, 14–16 thereby pointing to a neuroendocrine correlate of elevated stress sensitivity within these individuals. However, several studies could not replicate these initial findings 17–21 or have reported effects in the opposite direction. 22 As most of these experimental studies comprised small sample sizes and effects of single genetic variants are inherently small, 25 we consider a meta-analytic approach a significant contribution to this field of research. Based on above-reviewed findings and their potential implications for the understanding of biological pathways conveying disease risk, we aimed to evaluate the association between 5-HTTLPR genotype and HPA-axis reactivity to acute stress as well as the magnitude of this relationship by applying a meta-analytic technique. Moreover, we performed a formal testing for evidence of publication bias and explored potential moderating influences of participants’ age and sex. Department of Psychology, Technische Universita ¨ t Dresden, Dresden, Germany. Correspondence: Dr N Alexander, Chair of Biopsychology, Technische Universita ¨t, Dresden, Zellescher Weg 19, Dresden 01062, Germany. E-mail: alexander@biopsych.tu-dresden.de Received 4 May 2012; revised 5 July 2012; accepted 9 July 2012 Molecular Psychiatry (2012), 1–7 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp