Elsevier

Biological Psychiatry

Volume 59, Issue 8, 15 April 2006, Pages 673-680
Biological Psychiatry

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Brain-Derived Neurotrophic Factor–5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children

https://doi.org/10.1016/j.biopsych.2005.10.026Get rights and content

Background

Child abuse and genotype interact to contribute to risk for depression in children. This study examined gene-by-gene and gene-by-environment interactions.

Methods

The study included 196 children: 109 maltreated and 87 nonmaltreated comparison subjects. Measures of psychiatric symptomatology and social supports were obtained using standard research instruments, and serotonin transporter (5-HTTLPR) (locus SLC6A4) and brain-derived neurotrophic factor (BDNF) (variant val66met) genotypes were obtained from saliva-derived DNA specimens. Population structure was controlled by means of ancestral proportion scores computed based on genotypes of ancestry informative markers in the entire sample.

Results

There was a significant three-way interaction between BDNF genotype, 5-HTTLPR, and maltreatment history in predicting depression. Children with the met allele of the BDNF gene and two short alleles of 5-HTTLPR had the highest depression scores, but the vulnerability associated with these two genotypes was only evident in the maltreated children. A significant four-way interaction also emerged, with social supports found to further moderate risk for depression.

Conclusions

To the best of our knowledge, this is the first investigation to demonstrate a gene-by-gene interaction conveying vulnerability to depression. The current data also show a protective effect of social supports in ameliorating genetic and environmental risk for psychopathology.

Section snippets

Sample

Participants included 196 children: 109 children who were removed from their parents’ care within the past 6 months due to reports of abuse and/or neglect and 87 community control subjects with no history of maltreatment or exposure to intrafamilial violence. All the children included in our earlier report (n = 101) are also included in this investigation (Kaufman et al 2004), with the cohort approximately doubled since our prior publication, providing a more appropriate sample size to examine

Procedures

Participants underwent baseline interviews at their current place of residence. The Mood and Feelings Questionnaire was completed at the first baseline interview. The baseline data were collected in one session with the child and two sessions with the parent/guardian. The parent portion of the K-SADS-PL child psychiatric diagnostic interview was completed at the second session. At the end of the first baseline interview, children received $15 and parents received $25 as compensation for

Depression Diagnoses

The maltreated children were more likely to meet criteria for major depression, dysthymia, or depressive disorder not otherwise specified than the control subjects (any depressive disorder: maltreated: 35%; control subjects: 7%; χ2 = 19.7; df = 2; p < .01), and no children in the comparison cohort met full diagnostic criteria for major depression (MDD: maltreated: 13%; control subjects: 0%; χ2 = 10.3; df = 1; p < .006). The most common psychiatric diagnosis within the maltreated sample was

Discussion

In this study, depression severity in maltreated children was predicted by interaction between a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and the met allele of the BDNF val66met polymorphism and measures of the quality of children’s social supports. To the best of our knowledge, this is the first investigation to demonstrate gene-by-gene interaction in the development of depression symptomatology and one of the first investigations to show that

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      Consequently, a number of studies have now shown an association between the valine (Val)66-to-methionine (Met) variant (Val66Met) within the BDNF sequence (also referred to as BDNF G196A or rs6265) in particular and a variety of mental health related disorders, including eating disorders, schizophrenia and substance misuse (Gratacòs et al., 2007). Gene environment-interaction studies have also shown that a history of maltreatment and the Val66Met BDNF variant in particular, correlates positively with the development of depression (Kaufman et al., 2006) and a higher frequency of violent suicide attempts (Perroud et al., 2008). To further investigate whether the BDNF Val66Met polymorphism may also influence the effects of childhood maltreatment on BPD phenotype, Wagner et al. (2010c) compared BDNF genotype and impulsive aggression scores amongst a sample of BPD patients.

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