5-HTTLPR × stress hypothesis: is the debate over?

Ancelin, Marie-Laure; Ryan, Joanne

doi:10.1038/mp.2017.195

Cited by 15 publications

(15 citation statements)

References 11 publications

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“…For significant bivariate associations, we evaluated the effect of 5-HTTLPR by stratifying it into 3 genotypes (LL, SL and SS) because of a lack of consensus about the choice of a genetic model and frequent reports of heterosis for 5-HTTLPR. 36,37 To account for the fact that we examined multiple brain regions, we adjusted significance levels using the false discovery rate (FDR) method. 38 All tests were 2-sided, and we used SAS (version 9.4, SAS Institute, Inc.) for the statistical analyses.…”

Section: Discussionmentioning

confidence: 99%

“…The vast majority of the structural imaging genetic studies did not consider the SL genotype individually, despite a lack of consensus regarding the genetic model and frequent report of heterosis for 5-HTTLPR. 37 Heterogeneity in age is another potential source of concern: 48 in younger populations, the S allele is a risk factor for mental and physical distress, but the LL genotype appears to be a risk factor in elderly people, who are highly exposed to chronic disorders and severe stressors. 49 We found no significant volumetric differences according to 5-HTTLPR within groups (with or without lifetime MDD; data not shown) but we did find significant between-group differences.…”

Section: -Httlpr Genotypementioning

confidence: 99%

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Lifetime major depression and grey-matter volume

Ancelin

Carrière

Artéro

et al. 2019

jpn

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Background: There is evidence of structural brain alterations in major depressive disorder (MDD), but little is known about how these alterations might be affected by age at onset or genetic vulnerability. This study examines whether lifetime episodes of MDD are associated with specific alterations in grey-matter volume, and whether those alterations vary according to sex or serotonin transporter-linked promoter region (5-HTTLPR) genotype (LL, SL or SS). Methods: We used structural MRI to acquire anatomic scans from 610 community-dwelling participants. We derived quantitative regional estimates of grey-matter volume in 16 subregions using FreeSurfer software. We diagnosed MDD according to DSM-IV criteria. We adjusted analyses for age, sex, total brain volume, education level, head injury and comorbidities. Results: Lifetime MDD was associated with a smaller insula, thalamus, ventral diencephalon, pallidum and nucleus accumbens and with a larger pericalcarine region in both men and women. These associations remained after adjustment for false discovery rate. Lifetime MDD was also associated with a smaller caudate nucleus and amygdala in men and with a larger rostral anterior cingulate cortex in women. Late-onset first episodes of MDD (after age 50 years) were associated with a larger rostral anterior cingulate cortex and lingual and pericalcarine regions; early-onset MDD was associated with a smaller ventral diencephalon and nucleus accumbens. Some associations differed according to 5-HTTLPR genotype: the thalamus was smaller in participants with MDD and the LL genotype; pericalcarine and lingual volumes were higher in those with the SL genotype. Limitations: This study was limited by its cross-sectional design. Conclusion: Major depressive disorder was associated with persistent volume reductions in the deep nuclei and insula and with enlargements in visual cortex subregions; alterations varied according to age of onset and genotype.

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Section: Discussionmentioning

confidence: 99%

Section: -Httlpr Genotypementioning

confidence: 99%

Lifetime major depression and grey-matter volume

Ancelin

Carrière

Artéro

et al. 2019

jpn

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“…lifetime major depression and anxiety disorder, head injury, and cardiovascular ischaemic pathologies. Given the frequent report of heterosis for 5-HTTLPR due to multiple sources of interacting effect (epistasis, sex, childhood adversity …) (Ancelin & Ryan, 2018), the modifying effect of 5-HTTLPR was evaluated by stratification into three genotypes (LL, SL, and SS) as described (Ancelin et al, 2019(Ancelin et al, , 2017. To account for the multiple brain regions examined, we adjusted the significance levels using the false discovery rate (FDR) method (Benjamini & Hochberg, 1995).…”

Section: Discussionmentioning

confidence: 99%

Structural brain changes with lifetime trauma and re-experiencing symptoms is 5-HTTLPR genotype-dependent

Ancelin

Carrière

Artéro

et al. 2020

European Journal of Psychotraumatology

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2020) Structural brain changes with lifetime trauma and re-experiencing symptoms is 5-HTTLPR genotype-dependentABSTRACT Background: Findings on structural brain alterations following trauma are inconsistent due probably to heterogeneity in imaging studies and population, clinical presentations, genetic vulnerability, and selection of controls. This study examines whether trauma and reexperiencing symptoms are associated with specific alterations in grey matter volumes and if this varies according to 5-HTTLPR genotype. Methods: Structural MRI was used to acquire anatomical scans from 377 communitydwelling older adults. Quantitative regional estimates of 22 subregional volumes were derived using FreeSurfer software. Lifetime trauma was assessed using the validated Watson's PTSD inventory, which evaluates the most severe trauma experienced according to DSM criteria. Analyses adjusted for age, sex, total brain volume, head injury, and comorbidities. Results: Of the 212 participants reporting lifetime trauma, 35.4% reported re-experiencing symptoms and for 1.9%, this was severe enough to meet criteria for full threshold PTSD. In participants with the SS 5-HTTLPR genotype only, re-experiencing symptoms were associated with smaller volumes in middle and superior temporal, frontal (lateral orbital, rostral and caudal middle) and parietal (precuneus, inferior and superior) regions. The traumaexposed participants without re-experiencing symptoms were not significantly different from the non-trauma-exposed participants except for smaller precuneus and superior parietal region in traumatized participants and a larger amygdala in traumatized women specifically. Conclusions: In the non-clinical sample, lifetime trauma and re-experiencing symptoms were associated with smaller volume in prefrontal, temporal and parietal cortex subregions, and this varied according to serotonergic genetic vulnerability, 5-HTTLPR SS individuals being most susceptible.

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“…That the average age of onset of many adult psychological disorders occurs during this developmental period (e.g., Blakemore, 2018; Hooley et al, 2017), may have accounted for the adequate distribution of BSI scores with most falling in expected±one standard deviation of the normative sample (M = 50, SD = 10). On the other hand, however, age, which has emerged as an important factor influencing genetic expression of stress reactivity, has often been overlooked in study designs that have generally been limited to adolescents or young adult samples (Ancelin and Ryan, 2018). In a notable exception, Ancelin et al (2017) recently examined the effects of extrinsic stress and intrinsic stress (diurnal cortisol secretion) on current depression in a longitudinal, population-based study of 334 participants, age 65 or older, genotyped for 5-HTTLPR.…”

Section: Discussionmentioning

confidence: 99%

“…A more recent meta-analysis, however, failed to find support for increased risk of depression following childhood adversity in short allele carriers of 5-HTTLPR (Culverhouse et al, 2018). In fact, the Culverhouse et al meta-analysis, which included 31 studies totaling 38,802 individuals of European ancestry, did not replicate the widely-published finding of increased risk of depression following a stressful event for short allele carriers of 5-HTTPLR compared with long allele carriers (Ancelin and Ryan, 2018).…”

Section: Introductionmentioning

confidence: 92%

Risk and protective effects of serotonin and BDNF genes on stress-related adult psychiatric symptoms

Nestor

O'Donovan

Lapp

et al. 2019

Neurobiology of Stress

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We focused on individual risk by examining childhood adversity and current psychiatric symptoms in a sample of 100 college students genotyped for both the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF). Naturally occurring allelic variation in 5-HTTLPR (short/long) and BDNF (valine/methionine) have been strongly implicated in stress-related psychiatric risk, but the combined effects of these alleles on psychological functioning have yet to be fully elucidated. Univariate analysis revealed gene-environment correlations linking heightened psychiatric risk with past childhood adversity for short but not long 5-HTTLPR allelic carriers and for valine (Val) but not methionine (Met) BDNF allelic carriers. Multivariate analyses revealed a significant gene x gene interaction with results showing that risk varied systematically depending on both 5-HTTLPR and BDNF alleles, independent of childhood adversity. Hierarchical regression analyses indicated that approximately 11% of the variance in symptoms of depression could be specifically accounted for by the epistatic interaction of 5-HTTLPR and BDNF val66Met polymorphisms. Allelic group analyses indicated lowest risk, as measured by depression and anxiety, for allelic carriers of 5-HTTLPR-short and BDNF Met, followed by 5-HTTLPR-long and BDNF-Val, 5-HTTLPR-short and BDNF-Val, and 5-HTTLPR-long and BDNF-Met. Results suggest that protective or risk-enhancing effects on stress-related psychiatric functioning may depend on specific allelic combinations of 5-HTTLPR and BDNF.

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5-HTTLPR × stress hypothesis: is the debate over?

Cited by 15 publications

References 11 publications

Lifetime major depression and grey-matter volume

Lifetime major depression and grey-matter volume

Structural brain changes with lifetime trauma and re-experiencing symptoms is 5-HTTLPR genotype-dependent

Risk and protective effects of serotonin and BDNF genes on stress-related adult psychiatric symptoms

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