Article

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

Duke University, Durham, North Carolina, United States
Archives of General Psychiatry (Impact Factor: 14.48). 06/2005; 62(5):537-44. DOI: 10.1001/archpsyc.62.5.537
Source: PubMed

ABSTRACT

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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    • "There is evidence, albeit inconsistent, that allelic variation in the promoter of the serotonin transporter gene is associated with variation in hippocampal volume (Scharinger et al., 2010). There are reports of smaller (Eker et al., 2011; Frodl, Koutsouleris, et al., 2008; Taylor et al., 2005), larger (Frodl et al., 2004; Frodl, Zill, et al., 2008), and equivalent (Cole et al., 2011; Dutt et al., 2009; Frodl et al., 2010; Pezawas et al., 2005) volumes in S-allele carriers compared with their L-allele homozygous counterparts in both psychiatrically healthy and MDD groups. Although their findings are somewhat conflicting, these imaging genetics studies suggest the possibility that the allelic variation in the serotonin transporter gene could account for differences in hippocampal volume associated with risk for depression. "

    Full-text · Article · Jan 2015 · Journal of Abnormal Psychology
    • "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.
    No preview · Article · Jul 2014 · Neuroscience Letters
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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.
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