1. The Risk for Major Depression Conferred
by Childhood Maltreatment is Multiplied
by BDNF and SERT Genetic
Vulnerability: A Replication Study
By: Travis Green & Danielle Dunwald
What is Major Depression
● Depression is a whole body illness that affects a person’s physical health
-How one feels, thinks, and behaves towards others
● Person suffering from depression have problems
-Eating, sleeping, working, getting along with family and friends
● If they experience five of the following symptoms nearly everyday for a period
of at least two weeks
-Sad,low, empty moods,loss of interest in activities, feelings of
worthlessness and guilt, difficulty thinking concentrating or making decisions,
decreased energy, changes in appetite, insomnia, thoughts of death/suicide

2. Depression Facts
● Estimated 17.5 million Americans suffer from sort of depression
● 9.2 million have major or clinical depression
● 80% with clinical depression who seek treatment see improvement in their
condition
● Women will experience depression twice as much as men
● CDC states that suicide was the 9th leading cause of death
● Major Depression is 1.5-3.0 times more common among first degree
biological relative of those with the disorder than that of the general
population
● The economic cost is estimated 30.4 billion a year
Background Information
● SERT (serotonin transporter) gene plays part in the genotypic determination
of one’s likelihood of developing depression.
● BDNF (brain-derived neurotrophic factor) is a protein that is responsible for
helping in the brain with a plethora of different functions.
○ Learning/memory
○ neurogenesis
○ mood

3. Introduction
● Aims to clarify the interplay between SERT, BDNF, and childhood
maltreatment.
● Hypotheses:
○ In the presence of childhood maltreatment, those individuals carrying low function alleles for
both SERT 5-HTTLPR (biallelic or triallelic) and BDNF Val66Met polymorphisms would have a
higher risk for MD.
○ That the 3-way interactive model of depression would explain our outcome better than any
other model containing 5-HTTLPR, BDNF Val66Met and childhood maltreatment variables.
Methods

4. PredicD-Gene Study
● PredictD-gene study:
○ genetic substudy nested in larger cohort study
○ Objective: to develop a high risk algorithm for the onset of MD
○ 3-year prospective study
○ Assessments at 5 points (months):
■ first interview
■ 6
■ 12
■ 24
■ 36
Participants
● Samples were collected from 7 different Spanish provinces.
○ 41 health centres
○ 231 physicians
● Recruited from the PredictD-study
○ October 2005-February 2006
● Ages 18-75
● Excluded participants:
○ Couldn’t understand Spanish
○ Currently suffering from an organic mental disorder and/or terminal illnesses.

5. Assessing Participant Depression
● MD diagnoses was based on all criteria ascertained using the depression
section of the Composite International Diagnostic Interview
○ 6 month to lifetime diagnoses
Measuring Childhood Maltreatment
● 3 types of maltreatment collected in data
● Measures laid out with strict guidelines
● Measures were dichotimized:
○ Emotional
○ Physical
○ Sexual
● Emotional Group
● Physical Group
● Sexually Abused Group

6. Molecular Analyses (Everyone’s Favorite Part!!!!)
● Genotyping the Promoter Region of SERT:
○ DNA obtained from Saliva and Blood samples
■ 5-HTTLPR (L/S) biallelic polymorphism
■ 5-HTTLPR (LA
/LG
/S) triallelic polymorphism (rs25531)
○ Triallelic sample allowed for recheck of biallelic genotyping
○ 6 possible genotype combinations into 3 functional triallelic genotypes:
■ l/l = LA
/LA
■ l/s = LA
/LG
or LA
/S
■ s/s = LG
/LG
or LG
/S or S/S
○ Results are mainly reported using the SERT 5-HTTLPR triallelic polymorphism
Continued...
● Genotyping the BDNF Val66Met polymorphism:
○ TaqMan allelic discrimination assay from life technologies
● Testing for the validity and accuracy of genotyping
○ rested 10% random sample
○ both loci: 5-HTTLPR and BDNF Val66Met (rs6265) loci

7. Results
Participants
●

8. Main Effects of Genetic and Childhood Maltreatment
Risk Factors on MD
Two-Way and Three-Way interactions and Risks for
MD

9. Triallelic
Childhood Maltreatment and BDNF Val66Met SNP

10. SERT 5-HTTLPR triallelic, BDNF Val66Met SNP and
Childhood Maltreatment

11. Discussion
● Found consistent 3-way gene (SERT) X gene (BDNF)X Environment
(childhood maltreatments) interactions showing that combined genetic effect
modification on the risk for MD bestowed by several modalities of early
childhood mistreatment
● Strength of the study was the Face to Face interviews who were repeatedly
assessed thorough objective and validated instruments
-phenotypical characterization of both MD and childhood maltreatment
● Experiences of maltreatment during childhood to be associated with MD in
adults.
Discussion cont...
● Found an independent association between BDNF and the VAL66Met
variation and MD
● VAL/VAL carriers have significantly increased risk for MD compared to those
carrying the Met Allele.
● Recent studies have shown people homozygous for Met Allele may be
greater risk of MD than Val carrier alleles.
● VAL-to-MET mutation may increase susceptibility for MD, but only after early
life stress.
● BDNF variability shift to MET allele carriers when important environmental risk
factors for depression are taken into account.

12. Conclusion
● Results confirmed that the increase risk for major depression bestowed by
childhood maltreatment is modified by the variation at both SERT and the
BDNF genes.
● Individuals who carry both the SERT S allele and the BDNF are more
vulnerable of the impact of childhood maltreatment on their mental health
● Lastly, they pat themselves on the back and say that their findings strongly
support the SERT/BDNF stress-sensitivity hypothesis for depression
Questions?????????
I noticed that the participants for this study were only from Spain. Would you expect differing results if this study was done on people of
different ethnic backgrounds?
So both of the selected genes made children more susceptible to depression as a result of childhood maltreatment? What
conclusions/speculations would you draw about the actual function of this gene and how it affects the brain? Is it possible that this gene
affects personality traits in children? How useful is this study to other fields of research?
The participants were taken from Spain, do you think, since depression varies in wealthy and poor countries, that the results would be
different in a place like West Africa?
Could age difference factor into these results? I have seen many times that teens show higher level of depression, but this study uses
all ages.
After reading this study, do you think higher levels of BDNF result in less depression? In another class we read that SSRI’s result in
higher levels of BDNF, could this be a reason why anti-depressants work?

13. More Questions
As they mentioned, one downfall of the study was interviewing people of their childhood maltreatment, partly due to traumatic
experiences altering peoples’ memory. Did you find in any other studies a way to discover childhood maltreatment in a different way?
In this study they adjusted their data for age, sec and baseline MD. How exactly did they adjust for these different factors within the
population?
The researchers claim that their evidence supports their hypothesis that having both the s/* and Met/* gene in accordance with
childhood abuse increase risk of MD, however they only showed that conclusion in those who underwent childhood sexual abuse. They
did see very high results in both the ‘s/* and Met/*’ and the ‘s/* or Met/*’ so I am convinced there is a correlation, however was it correct
of them to state their conclusions using the blanket term of “childhood abuse”?
In accordance with the previous question, the results suggest that theirs was a much greater correlation between displaying both genes
of interest and having a history of childhood sexual abuse. Why do you think this form of abuse represented a great correlation in terms
of the genes of interest?
I understand that the relationship between SERT, BDNF, and the environment is the focus of this and many other studies of this kind,
but what is the mechanism proposed for how the polymorphisms in these genes result in depression when coupled with a stressful
environmental factor such as abuse?
Thank you for your time and Remember…..
https://www.youtube.com/watch?
v=ijZRCIrTgQc