Social Adversity, the Serotonin Transporter (5-HTTLPR) Polymorphism and Major Depressive Disorder

Strangeways Research Laboratory and University of Cambridge Department of Public Health and Primary Care, Worts Causeway, Cambridge, UK.
Biological Psychiatry (Impact Factor: 10.26). 03/2006; 59(3):224-9. DOI: 10.1016/j.biopsych.2005.07.014
Source: PubMed


Recent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.
Data were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.
One-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.
This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.

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    • "In recent years, studies have suggested an important interplay between genetic and environmental factors in the pathophysiology of MDD (Surtees et al., 2006). Epigenetic regulatory processes have now come into the spotlight to explain the mediating role of social environmental factors, such as childhood adversity or stressful life events, on gene expression (Carballedo et al., 2012b). "
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    ABSTRACT: Considerable evidence suggests a crucial role for the epigenetic regulation of brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD). However, the relationship between BDNF DNA methylation and white matter (WM) integrity in MDD has not yet been investigated. In the current study, we examined the association between the DNA methylation status of the BDNF promoter region and WM integrity in MDD. Sixty patients with MDD and 53 healthy controls underwent T1-weighted structural magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), to assess their WM integrity. BDNF DNA methylation at 4 CpG sites of the promoter region was also measured.As compared to healthy controls, the MDD group demonstrated reduced fractional anisotropy (FA) in the bilateral anterior and posterior corona radiata (ACR and PCR), genu of the corpus callosum, and the bilateral posterior thalamic radiations. We observed a significant inverse correlation between the DNA methylation of the BDNF promoter region and the FA of the right ACR in MDD patients.Our findings demonstrate a relationship between methylation of the BDNF promoter region and the integrity of the ACR, a key structural component of the emotional and cognitive control network involved in the pathophysiology of MDD. This correlation suggests that BDNF DNA methylation may contribute to structural WM changes in MDD patients.
    Journal of Affective Disorders 02/2015; 172. DOI:10.1016/j.jad.2014.09.042 · 3.38 Impact Factor
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    • "In our study, we only included cases that followed all the inclusion requirements, and cases with any deviation from our criteria were excluded. The excluded papers included 13 studies that were not for geriatric depression [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19], 3 brief reports or reviews [20] [21] [22] and 1 that is on Alzheimer's disease related depression [23]. We also excluded 3 studies that contained cases of unclear diagnosis of depression [24] [25] [26]. "
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    ABSTRACT: Serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is the genetic variant coding for the serotonin transporter and may play an important role in the etiology of depression. However, genetic studies examining the relationship between 5-HTTLPR polymorphism and geriatric depression have produced inconsistent results. We conducted a meta-analysis to compare the frequency of 5-HTTLPR variants in geriatric depression cases and non-depressed controls in the elderly. A total of 5 studies involving 579 geriatric cases and 1372 non-depressed controls met the inclusion criteria. With strong statistical power, pooled odds ratios (ORs) and 95% confidence intervals (CIs) for genotypic analyses (S carrier versus L/L, S/S versus L/L) were provided. The results of our analysis indicate statistically significant association between S allele and the risk of geriatric depression (OR ScarriervsS/S=1.29, 95% CI 1.01-1.66; OR S/SvsL/L=1.68, 95% CI 1.20-2.35). Our findings suggest that 5-HTTLPR polymorphism is of importance in the development of geriatric depression.
    Neuroscience Letters 07/2014; 578. DOI:10.1016/j.neulet.2014.06.046 · 2.03 Impact Factor
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    • "Relationship of NEO-FFI neuroticism score to 5-HTTLPR/rs25531 and amygdala rs-FC Although positive associations between the 5-HTTLPR s-allele and elevated trait negative affect could not consistently be demonstrated across studies (e.g.: Gillespie et al. 2005; Willis-Owen et al. 2005; Surtees et al. 2006; Munafò et al. 2009), some studies provided evidence for an association of the s-allele to anxiety related traits as neuroticism (Schinka et al. 2004; Gonda et al. 2009). Therefore, we tested for this association in our sample and examined whether genetically determined effects would replicate when using neuroticism as a behavioral correlate (as measured with the NEO- FFI). "
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    ABSTRACT: The s/s-genotype of the 5-HTTLPR polymorphism and the personality trait of neuroticism have both been associated with experiences of negative affect, anxiety and mood disorders, as well as an emotional processing bias towards negative facial emotions. On a neural level, this bias can be characterized by altered amygdala and fusiform gyrus (FFG) activity during perception of negative facial expressions. Using resting-state functional magnetic resonance imaging in a multi-center-sample of 178 healthy subjects of European descent, this study investigated the association of 5-HTTLPR (short s- and long l-allele) including the genotype of the single nucleotide polymorphism (SNP) rs25531 (A/G) within this region polymorphism, and trait neuroticism on resting-state functional connectivity (rs-FC) between amygdala and the FFG. Moreover, we aimed to identify additional brain regions with associations of 5-HTTLPR/rs25531 (combined according to its expression; low: s/s; high: lA/lA; intermediate: s/lA, s/lG, lG/lG, lA/lG) and trait neuroticism to amygdala rs-FC. Separate analyses for 5-HTTLPR/rs25531 and neuroticism (controlling for age, gender, handedness, and research site) revealed that s/s-homozygotes and individuals high in neuroticism obtained altered amygdala rs-FC in the right occipital face area, which is considered to be a "core component" of the face processing system. Importantly, effects of neuroticism were replicated across three independent research sites. Additionally, associations of 5-HTTLPR/rs25531 genotype and amygdala rs-FC were observed in the anterior and posterior cingulate cortex, whereas neuroticism was not related to rs-FC in these areas. The presented data implies that 5-HTTLPR/rs25531 variants and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus and suggests that variants of 5-HTTLPR/rs25531 genotype and different levels of neuroticism may partly account for altered processing of negative facial emotions.
    Brain Structure and Function 05/2014; 220(4). DOI:10.1007/s00429-014-0782-0 · 5.62 Impact Factor
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