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Polymorphisms in BDNF (Val66Met) and 5-HTTLPR, morning cortisol and subsequent depression in at-risk adolescents.

ABSTRACT: BACKGROUND:There is increasing evidence for genetic effects on the hypothalamic-pituitary axis system. More than one gene is likely to moderate corticoid-mediated activity. AIMS:To investigate whether the brain-derived neurotrophic factor (BDNF) polymorphism (rs6265, Val66Met) is associated with morning waking salivary cortisol and moderates the corticoid-mediated risk for subsequent depressive episode onset independently of the known effects of 5-HTTLPR (the serotonin transporter gene promoter). METHOD:High-risk adolescents (n = 401) were genotyped for Val66Met BDNF and 5-HTTLPR. Salivary samples were obtained on four consecutive school days within 1 h of waking. There were 365 (91%) remaining participants reassessed at 12 months for episodes of psychiatric disorder in the follow-up period. Of these, 357 (89%) had complete data for multivariate modelling. RESULTS:There were 41 (11.2%) individuals who reported a new episode of clinical depression over the follow-up period. Increased risk for subsequent depression was found in carriers of the Val66Val genotype in BDNF with higher morning waking cortisol. This remained present when the known interaction between carriers of a short allele of 5-HTTLPR with higher morning salivary cortisol was taken into account. CONCLUSIONS:Both BDNF and 5-HTTLPR genes show evidence of modifying the risk of a subsequent new depressive episode associated with elevated morning salivary cortisol. In adolescents morning salivary cortisol levels may constitute a biomarker for some forms of unipolar depression.

SUBMITTER: Goodyer IM

PROVIDER: S-EPMC2966502 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Polymorphisms in BDNF (Val66Met) and 5-HTTLPR, morning cortisol and subsequent depression in at-risk adolescents.

Goodyer Ian M IM Croudace Tim T Dudbridge Frank F Ban Maria M Herbert Joe J

The British journal of psychiatry : the journal of mental science 20101101 5

<h4>Background</h4>There is increasing evidence for genetic effects on the hypothalamic-pituitary axis system. More than one gene is likely to moderate corticoid-mediated activity.<h4>Aims</h4>To investigate whether the brain-derived neurotrophic factor (BDNF) polymorphism (rs6265, Val66Met) is associated with morning waking salivary cortisol and moderates the corticoid-mediated risk for subsequent depressive episode onset independently of the known effects of 5-HTTLPR (the serotonin transporter ...[more]

PMID: 21037213

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Project description:BACKGROUND:Despite research supporting moderate heritability of depression, efforts to replicate candidate gene associations to depression have yielded inconsistent results. We tested whether Val66Met and 5-HTTLPR exhibit utility as genetic markers of depression risk, testing for replicable associations to cognitive and interpersonal endophenotypes of depression (rumination and co-rumination), and further exploring developmental and sex moderation. METHOD:In Study I, 228 youth (ages 8-14) of mothers with or without a history of MDD during the child's lifetime were recruited from the community. Replication tests were carried out in Study II, a sample of 87 youth with similar recruitment. RESULTS:In Study I, the Val66Met single-nucleotide polymorphism (SNP) was associated with rumination in adolescents, but not children, such that adolescents homozygous for the Val allele reported higher rumination levels. Further, a cumulative genetic score (CGS) (Val66Val and 5-HTTLPR) predicted higher levels of co-rumination, specifically among adolescent girls. Both genetic associations maintained significance after covarying for current depressive symptomology, and the other endophenotype. Finally, both genetic associations exhibited similar effect sizes in Study II, although results did not reach statistical significance. CONCLUSIONS:RESULTS replicate a previously reported association between the brain derived neurotrophic factor (BDNF) Val allele and rumination in adolescents, and provide preliminary support for a CGS predictive of co-rumination in adolescent girls. The current study indicates that candidate genes may demonstrate utility as consistent genetic markers of depression risk when focused on specific phenotypes, and supports the need to explore potential differential effects of developmental stage and sex. However, given the small sample sizes and possibility of chance findings, these results should be interpreted with caution pending replication.

Project description:Post-traumatic stress (PTSD) disorder is a mental health condition that can occur after experiencing or witnessing a traumatic event. The 27-F earthquake that struck Chile in 2010 was one such event that had a significant impact on the mental health of the population. A study was conducted to investigate the prevalence of PTSD and its associated factors among survivors of this earthquake. The study was a longitudinal design, involving a sample of 913 patients aged 18 to 75 years who attended 10 Primary Care Centers in Concepción, Chile. The Composite International Diagnostic Interview (CIDI) was used to assess both depressive episodes (DE) and PTSD before and after the earthquake. The study also involved genotyping studies using saliva samples from the participants, specifically focusing on the Val66Met and 5-HTTLPR polymorphisms. Statistical analysis was performed to examine the association between different variables and the presence of PTSD. These variables included demographic factors, family history of psychiatric disorders, DE, childhood maltreatment experiences, and critical traumatic events related to the earthquake. The results showed that the incidence of post-earthquake PTSD was 11.06%. No significant differences were found between the groups of participants who developed post-earthquake PTSD regarding the Val66Met or 5-HTTLPR polymorphisms. However, a significant association was found between the concomitant diagnosis of DE and the development of post-earthquake PTSD. The presence of DE doubled the risk of developing post-earthquake PTSD. The number of traumatic events experienced also had a statistically significant association with an increased risk of developing post-earthquake PTSD. The study's limitations include the potential interference of different DE subtypes, the complexity of quantifying the degree of earthquake exposure experienced by each individual, and events entailing social disruption, such as looting, that can profoundly influence distress. In conclusion, the study found that PTSD following the 27-F earthquake in Chile was associated with a concomitant diagnosis of DE and the number of traumatic events experienced. The study did not find a significant association between PTSD and the Val66Met or 5-HTTLPR polymorphisms. The researchers recommend that mental health professionals should prioritize the detection and treatment of concomitant depressive episodes and exposure to critical traumatic events in survivors of disasters. They also suggest that further research is needed to better understand the relationship between genetic factors and post-disaster PTSD.

Project description:BackgroundCommon genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression.AimsTo determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women.MethodWe recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva.ResultsThere were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U-shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels.ConclusionsMorning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression.

Project description:BackgroundBrain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder.MethodsBrain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined.ResultsSubjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity.ConclusionsThis study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Dataset Information

Polymorphisms in BDNF (Val66Met) and 5-HTTLPR, morning cortisol and subsequent depression in at-risk adolescents.

Publications

Polymorphisms in BDNF (Val66Met) and 5-HTTLPR, morning cortisol and subsequent depression in at-risk adolescents.

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