Influence of Serotonin Transporter Promoter Region Polymorphisms on Hippocampal Volumes in Late-Life Depression

Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 06/2005; 62(5):537-44. DOI: 10.1001/archpsyc.62.5.537
Source: PubMed


Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) influence transcription and may play a role in the pathogenesis and course of depression. Recent research demonstrates that specific polymorphisms may be associated with differences in hippocampal volumes in subjects with depression.
To examine associations between 5-HTTLPR genotype and hippocampal volumes in elderly control subjects and elderly subjects classified as having early or late onset of depression.
Cohort study examining baseline characteristics.
Subjects were community dwelling and 60 years or older. Using a definition of early-onset depression as depression first occurring at 50 years or younger, we examined 72 subjects with early-onset depression, 63 subjects with late-onset depression, and 83 healthy control subjects.
All subjects underwent genotyping for the 5-HTTLPR and underwent brain magnetic resonance imaging. Analyses of hippocampal volumes were controlled for total cerebral volume, age, and sex.
The interaction between diagnosis and 5-HTTLPR genotype was statistically significant for the right hippocampus (P = .04). Subjects with late-onset depression who were homozygous for the long (L) allele (L /L genotype) had significantly smaller right hippocampal volumes than did L /L subjects with early-onset depression (P = .046) or L /L control subjects (P = .01). Post hoc analyses showed that later age of depression onset was associated with smaller hippocampal volumes in subjects with the L /L genotype, but earlier age of onset was associated with smaller hippocampal volumes in subjects who were homozygous for the short (S) allele (S/S genotype).
Subjects with late-onset depression who were homozygous for the L allele exhibited smaller hippocampal volumes than other groups. Genotype also mediated the effect of age of onset on hippocampal volumes. Our findings differ from previous work; however, we examined an older and larger cohort of subjects than previous studies. Possible explanations for these findings include interactions between the serotonergic system and neurotrophic factors or cortisol response to stresses, each of which may affect hippocampal volumes.

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Available from: Warren Taylor, Dec 16, 2014
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    • "Study (author, year) Ethnic Depression Measure Case Control L/L L/S S/S L/L L/S S/S Taylor et al., 2005 [31] "
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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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    • "The relationship between the hippocampus and environmental stressors may be moderated by genetic factors. The serotonintransporter-linked polymorphic region (5-HTTLPR) has been shown to moderate the relationship between SLE and depression (Caspi et al., 2003), and is associated with smaller hippocampal volumes in adult (Eker et al., 2011) and elderly depressed subjects (Taylor et al., 2005). However, few studies have examined the effects of gene-by-stress interactions on the hippocampus. "
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    ABSTRACT: Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.
    Journal of Psychiatric Research 03/2013; 47(6). DOI:10.1016/j.jpsychires.2013.02.008 · 3.96 Impact Factor
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    • "Gallinat et al. [18] found lower hippocampal N-acetylaspartate (NAA, considered a mitochondrial marker and a reflection of neuronal density) levels among S allele carriers compared to those homozygous for the L allele [18]. Taylor et al. [67] reported a significant interaction between depression and 5-HTTLPR genotype in older adults, such that S/S predicted smaller hippocampal volumes for those with early-onset depression whereas L/L predicted smaller volumes for those with late-onset depression. In a relatively younger sample (mean age 33.6 years) [11], found a gene by depression interaction, with smaller hippocampi among depressed S/S individuals. "
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    ABSTRACT: Background: The short (S) allele of the serotonin transporter gene (5-HTTLPR) is associated with reduced serotonin turnover compared to the long (L) allele in Caucasians. Few studies have examined its impact on memory and brain structure in healthy young adults. Methods: Participants included 51 healthy young adults (25 female; ages 18-25). Multiple regressions examined the independent contribution of 5-HTTLPR biomarker genotype and its interactions with gender and sub-clinical depressive symptoms on hippocampal volumes and memory. Results: The 5-HTTLPR genotype significantly interacted with gender in predicting larger left hippocampal volumes in S-carrying females and smaller hippocampal volumes in males (p<.03). Gender also moderated the impact of the 5-HTTLPR on neurocognition. In females, S allele carriers had poorer visual recall compared to L carriers (p<.05). A three-way interaction between 5-HTTLPR, gender, and depressive symptoms was also observed (p<.04). In females, larger left hippocampal volumes were associated with increased depressive symptoms while the opposite was seen in males. Finally, in male and female S carriers, increased depressive symptoms were marginally associated with poorer verbal memory (p<.09). Conclusions: In females, the 5-HTTLPR S allele was associated with poorer memory performance, increased depressive symptoms and larger hippocampal volumes. In males, the S allele predicted smaller hippocampal volumes and increased depressive symptoms. The opposite morphometric patterns likely reflect gender differences in adolescent hippocampal development. Larger longitudinal studies are needed to examine whether the impact of 5-HTTLPR genotype on neurocognition across development differs according to extent of mood symptoms and gender.
    Behavioural brain research 12/2012; 242(1). DOI:10.1016/j.bbr.2012.11.013 · 3.03 Impact Factor
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