Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis.

0.69 MB·English

by  Hosang, Georgina M

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RESEARCH ARTICLE Open Access
BDNF
Interaction between stress and the
Val66Met polymorphism in depression:
a systematic review and meta-analysis
Georgina M Hosang1,2*, Celia Shiles3, Katherine E Tansey2,4, Peter McGuffin2 and Rudolf Uher2,5
Abstract
Background: Major depression is a disabling psychiatricillness withcomplex origins. Life stress(childhood
adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stressand
Val66Met polymorphismin thebrain-derived neurotrophic factor (BDNF) gene has receivedmuch attention.
The aim of thepresentwork was to review and conduct a meta-analysis on theresults from published studies
examining this interaction.
Methods: A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013.A
total of 22 studies witha pooled total of14,233 participants met theinclusion criteria, theresults of which were
combined and a meta-analysis performed using the Liptak-Stoufferz-score method.
Results: The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between
life stress and depression (P=0.03). When the studies were stratified bytypeof environmental stressor, the
evidence was stronger for an interaction withstressfullife events(P=0.01) and weaker for interaction of BDNF
Val66Met with childhood adversity (P=0.051).
Conclusions: The interactionbetween BDNF and life stress in depression is stronger for stressful life events rather
than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.
Keywords: Stress, Life events, Childhood maltreatment, Childhood adversity, Child abuse, Depression, Brain-derived
neurotrophic factor, BDNF, rs6265,Gene-environmentinteraction
Background neurotrophic factor (BDNF) gene has been implicated in
Major depression is a prevalent psychiatric illness that is stressvulnerability[8].Bothvariationinthisgenesequence
associated with considerable morbidity and mortality [1]. and stress exposure influence expression and intracellular
Much research has been dedicated to uncovering its trafficking of the BDNF protein. Stress is hypothesised to
aetiology with mixed success. Environmental factors, cause a reduction in BDNF (protein) levels in the brain
such as childhood adversity [2,3] and stressful life events (particularly in regions linked to emotion), which alters
[4-6] have been associated with the onset and course of mood and may cause depression [9]. Consequently, the
major depression. However, not everyone exposed to such BDNF gene has been identified as a stress vulnerability
adversitydevelopsthisillnessorrelapses[6];thishasledre- candidate generating much research, which has yet to
searchers to explore stress vulnerability factors, including bereviewedorsynthesised.
interactions with genetic influences [7]. The brain-derived The purpose of the present work was to systematically
review and perform a meta-analysis on studies that
have investigated the interaction between the Val66-
*Correspondence:[email protected] Met polymorphism in the BDNF gene and life stress
1PsychologyDepartment,Goldsmiths,UniversityofLondon,NewCross, (childhoodadversityandstressfullifeevents)indepression.
LondonSE146NW,UK
Major depression has a lifetime prevalence of 17% [10]
2MRCSocial,GeneticandDevelopmentalPsychiatryCentre,Instituteof
Psychiatry,King’sCollege,London,DeCrespignyPark,LondonSE58AF,UK and is diagnosed based on the presentation of depressive
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symptoms (for example, low mood, sleep disturbance and depressive episode [6,24]. Although it has been shown
suicidalbehaviours)thatlastatleast2weeks[1].Depressive that stressfullifeeventsclusterbeforeadepressiveepi-
episodes are also experienced by individuals suffering sode or worsening of symptoms [4,25], there is strong
frombipolardisorder,althoughthedefiningfeatureofthis evidence that one such event is sufficient to trigger an
conditionismania(symptomsinclude,elation,grandiosity episodeonset[26].
andirritability)[11]. Investigating the relationship between stressful events
Major depression is considered one of the most burden- and depression is not as straightforward as establishing
somediseasesintheworld[12]anditisprojectedthatthis whether an event occurred or not, various elements must
illness will be the second leading cause of disease burden be considered. Determining the direction of association is
fordevelopedcountriesby2020[13].Betterunderstanding important, are stressful events generated by the individual
of the aetiology of this debilitating disorder is urgently andinfluencedbydepressivesymptoms(dependentevents),
requiredsothatstepscanbetakentoreducetheburden or is it that such events occur ‘out of blue’ and trigger
ontheindividual,theirfamiliesandsocietyasawhole. depressive episodes (independent events)? Establishing
theeventseverityisessentialastheirimpactdiffersbe-
Lifestressanddepression tween individuals and is dependent on circumstance.
There is a wealth of literature concerned with the im- Thesekeyissuesareaddressedwiththe collectionofcon-
pact of life stress and depression, with studies focusing textualandbiographicalinformationbestachievedusing
onchildhoodadversityandstressfullifeevents. semi structured interviews [27-29]. Studies employing
this method have consistently shown that severe inde-
Childhoodadversity pendent events are linked to the onset, relapse and ex-
Childhood adversity is defined as stressful experiences acerbationofdepressivesymptoms[5,25,30],illustrating
that occur early in life; examples include abuse (such as acausalrelationship.
sexual and physical abuse), neglect (failure of caretakers to There is strong evidence for an association between
providethechildwithbasicneedssuchasfoodorsupport), life stress and depression, research now focuses on iden-
parental death and divorce. Significantly higher rates tifying stress vulnerability factorsindepression including
of childhood adversity are reported by adults with geneticfactors[31,32].
majordepressioncompared to thegeneralpopulation[14].
Childhoodadversityisalsoassociatedwithworsecourseof Gene/environmentinteractions
depression, including lack of treatment response as well as Genetic sensitivity to one’s environment or gene-
morechronicandmorefrequentepisodes[15]. environment interactions [33], has spurred much mental
Most studies in this area rely on retrospective reporting healthresearchfollowingCaspiandcolleagues’[31]study.
whichisassociatedwithvariousbiasescallingintoquestion Their results showed that the low expressing short allele
the validity and reliability of their findings. A recent study of the serotonin-transporter-linked promoter region poly-
showed that whether childhood maltreatment is assessed morphism(5-HTTLPR;afunctionalvariantintheserotonin
prospectively (child protection database) or retrospectively transporter gene) increased depressive symptoms, rates of
(self-report), it is still significantly associated with major diagnosed depression and suicidality following exposure to
depression to a similar degree [16]. Moreover, Widom and stressfuleventsandchildhoodmaltreatment[31].
colleagues [17] prospectively followed children who were Many studies that attempted to replicate these results
abusedorneglected(identifiedthroughcourtrecords),and adopted different designs using divergent samples/
foundthatasadultstheseindividualswereatincreasedrisk populations, which resulted in mixed success [34,35].
ofmajordepressioncomparedtomatchedcontrols. Thereviews[7,28,36] and meta-analyticstudies [15,37]
Childhoodadversityisanon-specificriskfactorandhas published on this topic suggest that the interaction is
been linked to other emotional problems [18], psychiatric strongest between 5-HTTLPR and childhood adversity,
illnesses[16,19,20]andphysicaldisorders[21,22].Abetter rather than recent stressful events [37]. Life stress assess-
understanding of the specific mechanisms that underlie ment is crucial, with studies that used objective measures
thechildhoodadversity/depressionassociationisneeded. or semi structured interviews rather than crude self-
reportquestionnairesdetectingtheinteractionwiththe5-
Stressfullifeevents HTTLPRvariant [37]. The relationship between life stress
Stressfullifeeventsaredescribedascircumstancesthathave and the serotonin transporter gene is fairly consistent for
a negative impact on an individual (for example, stress) persistentandrecurrentdepression[14,38,39].
that occur close to the onset or relapse of the illness Other genes havebeenimplicatedin stressvulnerability
[23]. Stressful events such as bereavement and divorce including the CRHR1 [40,41],FKBP5 [42] and BDNF [43]
are common, but people’s responses to such events genes. The relationship between the Val66Met variant in
vary, some appear to cope well and others spiral into a the BDNF gene and stress in depression has been widely
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researchedandthusasystematicreviewandmeta-analysis Methods
iswarrantedtosynthesisetheliterature. Datasourcesandsearchstrategy
The systematic review was performed according to the
BDNFandlifestressindepression ‘Preferred Reporting Items for Systematic Reviews and
BDNF is a protein involved in the proliferation, differ- Meta-Analyses’ (PRISMA) guidelines [61]. The literature
entiation and survival of neuronal cells and regulation searcheswereundertakenusingPsychINFO,andPubMed
of synaptic plasticity and connectivity in the adult brain up until 22 November 2013 for original research studies.
[44].ResearchsuggeststhatBDNFmayalsobeinfluential Thesearchtermsweresynonymsfordepression,lifestress
insensitivitytostress. and the BDNF Val66Met polymorphism (see Table 1).
According to the ‘neurotrophic hypothesis’ of de- These terms were searched for in the articles’ titles,
pression [8,45], stress reduces BDNF activity, which keywords, tests and measures. Only papers published
results in decreased function in limbic brain regions in the English language were considered for inclusion. The
(forexample,hippocampus)involvedinemotionprocessing reference lists of identified studies were also searched by
and cognition. This reduction in turn is posited to be handforrelevantpapers.
associated with depressed mood; while antidepressant
therapy is hypothesised to reverse this effect [9,45]. Eligibilitycriteria
There is evidence that stress and trauma result in de- The eligibility criteria were stipulated as follows: utilisation
creased BDNF levels in both rodents [46,47] and humans of human participants; depression (illness onset or relapse)
[48,49]. The findings from several meta-analyses show or its symptoms were assessed; focus on BDNF Val66Met
that lower serum BDNF levels are detected among de- polymorphism (rs6265); childhood adversity and/or
pressed patients relative to controls but these levels stressful life events (a range of types of events) were
are normalised with antidepressant treatment [50,51]. assessed; the interaction between stress and the BDNF
There is some debate surrounding the link between Val66Met polymorphism was investigated. Studies in
BDNF, antidepressants and (hippocampal) neurogenesis gross departure of Hardy-Weinberg equilibrium were
(see [52] for more a detailed discussion). Together the excluded(forexample,P≤0.001).
evidencepresentedgenerallysupportsthe‘neurotrophic
hypothesis’ofdepression. Dataextraction
Asinglenucleotidepolymorphism(SNP)intheBDNF Variety of data were extracted from included studies in
gene (that is, Val66Met; rs6265) has been shown to in- accordance with other gene-environment interaction re-
fluence the activity of the BDNF protein. This SNP re- views [37,62] (see Table 2). When publications reported
sults in the substitution of valine (Val) to methionine resultsforbothchildhoodadversityandrecentstressfullife
(Met) [53]. Although the BDNF gene consists of several events they were included in each environmental stressor
polymorphisms many are in high linkage disequilibrium group; but the results for each stressor were averaged and
andhighlycorrelated[54,55]. included in the overall analyses. The data was extracted
The Met allele of the BDNF Val66Met polymorphism and confirmed by two authors (GMH and KET). Where
has been linked with reduced BDNF activity [44], memory studies used multiple life stress and/or depression
impairment [56] and harm avoidance [57]. Individuals with measures, the data yielded from interviews was in-
at least one Met allele of this SNP and at high risk of cluded in the analyses. If the information required was
affectivedisorders(co-twindiagnosedwithamooddisorder) not reported or unclear the authors of the original art-
have elevated evening cortisol levels,which suggests altered iclewerecontacted.
stressresponse[58].
TransgenicmicethatareMetcarriersofBDNF Val66- Qualityappraisalofstudies
Met exhibit increased anxiety-related behaviours under Themethodologicalqualityofincludedstudieswasevalu-
stress conditions [59], as well as decreased BDNF levels atedagainstaqualitychecklist,derivedfromtheSTREGA
in the hippocampus [60], in line with the ‘neurotrophic (‘Strengthening the Reporting of Genetic Association
hypothesis’. Studies’) and STROBE (‘Strengthening the Reporting of
The research highlighted thus far presents a case for a ObservationalStudiesinEpidemiology’)checklists[63,64],
significant interaction between BDNF Val66Met and which have been used by other gene-environment inter-
life stress in depression. The purpose of the current actionmeta-analyses[37].
paper is to systematically review and meta-analyse the In accordance with current guidelines and previous re-
literature concerned with this interaction addressing views of gene-environment interaction studies [37], the
the specific question: ‘is there a significant interaction studies were not weighted by quality scores or excluded
between the Met variant of BDNF Val66Met and life based on low scores, but the information is presented in
stressindepression?’ Additionalfile1forreaders’evaluation.
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Table1Termsusedforliteraturesearch between the fail-safe and the actual number of studies
Keyword(s) Additionalsearchtermsused published provides an estimation of the possibility of
publicationbiaseffectingourfindings.
1.Depression DepressivedisorderORmajordepressive
disorderORdepressionORmajordepressionOR
unipolardepressionORdepressivesymptoms Results
2.Lifestress Stressfullifeevents,ORlifeeventsORnegative Studyselection
lifeeventsORadverselifeeventsOReventsOR
Acombinationofthepredefinedsearchterms(depression+
stressORstressorsORchildhoodmaltreatment
ORchildhoodadversityORchildhoodstressOR lifestress+BDNFVal66Met)resultedin1,019hits;afterdu-
childabuseORchildneglectORadversity plicates were removed, 236 studies remained (see Figure 1).
3.BDNFVal66Met Brain-derivedneurotrophicfactorgeneORBDNF The abstracts of these articles were reviewed and those
polymorphism ORrs6265ORVal66Met studiesthatreportedontheinteractionbetweenlifestress
and BDNF Val66Met in depression were included. No
existingsystematicormeta-analyticreviewswerefound.
Statisticalanalyses
The Liptak-Stouffer z-score method was used to combine OverallevidenceforBDNF×stressinmooddisorders
studies at the level of significance tests with the results Out of the 22 studies included, 8 reported a significant
weighted by sample size. This approach has been used by interactionbetweenlifestress(eitherlifeeventsorchild
another meta-analysis of gene-environment interactions adversity) and the Met variant of BDNF Val66Met in
[37].Thismethodinvolvesanumberofsteps.First,the depression(seeTable2andFigure2).
P values from the eligible studies were extracted and Other studies provided partial evidence of a signifi-
converted to one-tailed values, with those less than cant stress×BDNF for specific types of depression [65],
0.50 indicating greater Met allele stress sensitivity and childhoodadversity[66,67]ordetectedagenderspecific
P values of greater than 0.50 corresponding to Val allele effect[68].
stresssensitivityindepression.Second,theseP valueswere Several studies found a significant interaction between
transformed into z-scores using a standard normal curve. life stress and BDNF in depression using aVal recessive
Positive z-scores were assigned to P <0.50 and negative model [69-71]. The allele frequencies of the BDNF
z-scorescorrespondedtoP>0.50.Third,thez-scoreswere Val66Met polymorphism differs between ethnic groups,
combined and weighted to take into account the study withtheMetallelefrequencyhighestamongAsianpop-
samplesize.Thefollowingformulawasusedtodothis: ulations [72]. Two of these studies used either a Han
X Chinese sample [69], or a cohort with mixed ethnicity
k
wz [71], which may have contributed to the unusual finding
i i
Zw¼qffiXffiffiffiiffi¼ffiffi1ffiffiffiffiffiffiffiffiffiffiffi withaValrecessivemodel.
k
w2
i¼1 i
Meta-analysisresult
The weighting factor w corresponds to each study’s Combining the results from the identified studies with a
i
sample size, k indicates the number of total studies, and total of 14,233 participants showed that the interaction
Z corresponds to the z-scores of individual studies. Z , between the Met variant of the BDNF Val66Met poly-
i w
which is the outcome of this test, follows a standard nor- morphismsignificantlymoderatestherelationshipbetween
mal distribution and thus related probability corresponds lifestressanddepression(P=0.03).Whenfindingsfrom
with a standard normal distribution table. This approach studiesthat used Caucasiansamplesweremeta-analysed
wasusedontheoverallandstratifiedanalyses. separately(toaccountforthepotentialconfoundingeffect
Sensitivity analyses were undertaken to determine of population stratification), the results failed to reach
whether the results were considerably influenced by conventional level of significance although they were
any single study; the procedure involved systematically intheexpecteddirection(P=0.07).
excluding each study and recalculating the significance The sensitivity analyses showed that the results
oftheresult. remained significant after removing each studyinturn
To assess the potential impact of publication bias on (>0.004 P <0.049) with the exception of 4 studies
the meta-analysis results the fail-safe N was calculated [43,73-75]. In terms of publication bias, to make these
for all analyses. In line with Karg and colleagues [37], results non-significant (P=0.05), more than 11 unpub-
the number of studies with a P value equal to 0.50 and lished or undiscovered studies with an average sample
a sample size of 647 (average sample size ofthe studies of 657 participants reporting a non-significant finding
analysedintheoverallmeta-analysis)werecalculatedthat (P=0.50) would need to exist. This corresponds to a fail-
wouldneedtobeincludedintheweightedLiptak-Stouffer saferatioof2studiesnotincludedinthemeta-analysisfor
analyses to obtain a non-significant result. The ratio everyincludedstudy.
Table2Summaryofstudiesexaminingtheinteractionbetweenlifestressandbrain-derivedneurotrophicfactor(BDNF)Val66Metindepression hH
ttpos
Source N Females,% Aasgseesastmsetundty Ancestry Studydesign Stressor Lifestressassessment Outcome Aonvee-rsaigdeedd ://wang
(Meanorrange) Pvalue ww et
Kaufmanetal.,2006[79] 194 51 9.3years Mixed Cross-sectional Childhoodadversity Childrentakenintocare Depressivesymptoms 0.6765 .bio al.B
m M
Kimetal.,2007[43] 732 59 65yearsandover EastAsian Cross-sectional Stressfullifeevents qReuseesatirocnhnera-iaredministered Depressiondiagnosis 0.000315 edce CMe
n d
Wichersetal.,2008[73] 464 100 18to46years European Longitudinaltwinstudy Childhoodadversity Questionnaire Depressivesymptoms 0.009 tral.c icine
Aguileraetal.,2009[66] 470 55 22.9years European Cross-sectional Childhoodadversity Questionnaire Depressivesymptoms 0.637 om20
Bukhetal.,2009[82] 290 66 38.5years(median) European Caseonly Stressfullifeevents Interview Depressiononset 0.004 /17414,1
12
Gattetal.,2009[88] 374 51 36.2years European Cross-sectional Childhoodadversity Questionnaire Depressivesymptoms 0.272 -7:7
0
Hosangetal.,2010[75] 1,085 62 37.83years European Case–control Stressfullifeevents Researcher-administered Bipolardisorderrelapse 0.02 15
questionnaire /1
2
/7
Lavebrattetal.,2010[68] 950 58 20to64years European Longitudinalsurvey Childhoodadversity Questionnaire Depressivediagnosis 0.5
andStressfullifeevents
Nederhofetal.,2010[80] 1,096 53 16.13years European Longitudinalstudy Childhoodadversity Questionnaires Depressivesymptoms 0.3525
andinterviews
Carveretal.,2011[76] 133 74 18.71years Mixed Cross-sectional Childhoodadversity Questionnaire Depressiondiagnosis 0.01
Elzingaetal.,2011[81] 1,435 69 42.2years European Caseonly Childhoodadversity Interview Depressiondiagnosis 0.4325
andstressfullifeevents andsymptomseverity
Juhaszetal.,2011[74] 1,269 70 34.04years Caucasian Cross-sectional Childhoodadversity Questionnaire Depressiondiagnosis 0.13165
andstressfullifeevents
Chenetal.,2012[69]a 780 51 13.6years HanChinese Longitudinaltwinstudy Stressfullifeevents Questionnaire Depressivesymptoms 0.9875
Grabeetal.,2012[70]a 2,035 53 55.6years Caucasian Caseonly Childhoodadversity Questionnaire Depressivesymptoms 0.785
Herbertetal.,2012[83] 279 100 36.8years Caucasian Longitudinalstudy Stressfullifeevents Interview Depressiondiagnosis 0.0935
Pereaetal.,2012[77] 302 50 18years Mixed Cross-sectional Childhoodadversity Questionnaire Depressivesymptoms 0.01725
(Columbian andstressfullifeevents
population)
Quinnetal.,2012[65] 240 59 40.01years Unknown Cross-sectional Childhoodadversity Questionnaire Melancholicsubtypeof 0.5
depressiondiagnosis
Caldwelletal.,2013[71]a 124 66 21.97years Mixed Cross-sectional Childhoodadversity Questionnaire Depressivesymptoms 0.8705
Comascoetal.,2013[67] 1,393 50 17to18years European Cross-sectional Childhoodadversity Questionnaire Depressivesymptoms 0.251
LaGrecaetal.,2013[78] 116 54 8.85years Mixed Cross-sectional Childhoodadversity Questionnaire Depressivesymptoms 0.167833
Jiangetal.,2013[89]a 238 73 61.7years Caucasians Cross-sectional Stressfullifeevents Carerofperson Depressivesymptoms 0.9805
withdementia
Brownetal.,2013[85] 234 100 37years Caucasian Longitudinalstudy Childhoodadversity Interview Depressiveepisodeonset 0.431
andstressfullifeevents
P
a
Total 14,233 g
e
5
Averagesamplesize 647 0.03 o
f
aTestedValrecessivemodel. 11
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Figure1Flowdiagramofstudiesconsideredforinclusion.Thisflowdiagramdepictseachstepintheprocessofstudyselection.
Since there is evidence for the differential interaction Childhoodadversity
effect with child adversity and stressful life events with Inall,16studiesexploredtheinteractionbetweenchildhood
other SNPs (for example, 5-HTTLPR [43]), the results adversityandBDNFindepression,4reportedasignificant
pertaining to the impact of these types of stressors and effect [73,74,76,77] and 5 showed partial support for this
theBDNFgenewereexamined. interaction[65-68,78](seeTable3).
Figure2ForestplotforincludedstudiesexaminingtheinteractionbetweentheMetvariantofthebrain-derivedneurotrophicfactor
(BDNF)geneandlifestressindepression.
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Table3Studiesincludedinthechildhoodadversity of 7,594 individuals; 5 uncovered a significant effect
meta-analysis (seeTable 4). The majority of these studies used either
Source Samplesize One-sidedPvalue researcher-administered questionnaires [43,75] or in-
Kaufmanetal.,2006[79] 194 0.6765 terviews [82], while the non-replicating studies relied
onself-reportchecklistswithoneexception[83].
Wichersetal.,2008[73] 464 0.009
Bipolardisorderwasthefocusofonestudy[75],which
Aguileraetal.,2009[66] 470 0.637
found that the effect of stressful life events on episodes
Gattetal.,2009[88] 374 0.272
ofbipolardepressionweresignificantlygreaterinMetallele
Lavebrattetal.,2010[68] 642 0.5 carriers (Met/Met and Val/Met) relative to those with the
Nederhofetal.,2010[80] 1,096 0.3525 Val/Val genotype. However, no such pattern was reported
Carveretal.,2011[76] 133 0.01 formanicepisodes[75].
Juhaszetal.,2011[74] 1,269 0.0018
Stressfullifeevents:meta-analysisresults
Elzingaetal.,2011[81] 1,435 0.435
A significant interaction between stressful life events and
Grabeetal.,2012[70] 2,035 0.785 the Met variant of BDNF Val66Met (P=0.01) was found;
Quinnetal.,2012[65] 240 0.5 the results remained significant when the analyses were
Pereaetal.,2012[77] 302 0.016 restrictedtostudiesusingCaucasiansamples(P=0.027).
LaGrecaetal.,2013[78] 116 0.167833 SensitivityanalysisshowedtheP valueremainedsignifi-
cant with the exclusion of each study from the analysis
Caldwelletal.,2013[71] 124 0.8705
(>0.001P<0.023),exceptfor2[43,75].
Comascoetal.,2013[67] 1,393 0.251
For this result to be non-significant (P=0.05) more
Brownetal.,2013[85] 234 0.431
than 14 unpublished or unidentified studies need to
Total 10,521 exist with an average sample of 690 participants and a
Averagesamplesize 658 0.051 non-significant result (P=0.50). This corresponds to a
fail-safe ratio of 1 study not included for every study
For instance,ratherthaninvestigatingchildadversity enteredintothemeta-analysis.
asoneoverarchingconstruct,Aguileraandcolleagues[66]
focused on different types and only found a significant Discussion
interaction between child sexual abuse and BDNF. A total of 22 studies with a combined sample of 14,233
Giventheacknowledgedheterogeneityinmajordepression participantsmettheeligibilitycriteria,8ofwhichreported
[1], Quinn and associates [65] explored the impact of a significant interaction between life stress and the Met
the child adversity-BDNF interaction on different sub- variant of BDNF Val66Met. The overall meta-analysis
types of the disorder and found a significant effect for found evidence for a significant interaction between life
non-melancholicdepressiononly. stress and BDNF in depression using a Met dominant
The childhood adversity measures used by studies is
particularly noteworthy, with all of the those reporting a
Table4Studiesincludedinthestressfullifeevents
significant interaction relying on questionnaires, while
meta-analysis
manyofthosestudiesnotreportinganeffectutilisedmore
Source Samplesize One-sidedPvalue
objectivemethods[79-81].
Kimetal.,2007[43] 732 0.000315
Childhoodadversity:meta-analysisresults Bukhetal.,2009[82] 290 0.004
In meta-analysing the results from included studies with Hosangetal.,2010[75] 1,085 0.02
a combined sampleof10,521 individuals, a trend towards Lavebrattetal.,2010[68] 950 0.5
a significant interaction between childhood adversity and
Juhaszetal.,2011[74] 1,269 0.2615
BDNFindepressionwasdetected(P=0.051),butwasnot
Elzingaetal.,2011[81] 1,435 0.43
improved on when only those studies with Caucasian
sampleswereanalysed(P=0.08). Chenetal.,2012[69] 780 0.9875
Inundertakingsensitivityanalyses, the resultsremained Pereaetal.,2012[77] 302 0.0185
non-significant after removing each study in turn (>0.052 Herbertetal.,2012[83] 279 0.0935
P<0.27),withtheexceptionof6[66,68,70,71,79,81]. Jiangetal.,2013[89] 238 0.9805
Brownetal.,2013[85] 234 0.0004
Stressfullifeevents
Total 7,594
The stressful events-BDNF interaction in depression
Averagesamplesize 690 0.01
wasinvestigatedin11studiesusingacombinedsample
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model.Whentheanalyseswerestratifiedbytypeofstres- ofadversityanddepressionsubtypesaswellasinvestigating
sor,theresultswerestrongestforstressfullifeeventswhile genderdifferences.
the effect of childhood adversity failed to reach conven- The non-replicating studies have two characteristics
tionallevelsofsignificance. that are noteworthy. Firstly, some studies which failed to
Thesefindingshelpbuildalifespanmodelofcausation detect any evidence for a child adversity×BDNF in
for major depression focusing on several gene-stress depression used child and adolescent cohorts [79,80].
interactions. Research shows that childhood adversity Secondly, more reliable (for example, interviews [80,81])
(distalandstableriskfactor)significantlyinteractswiththe and objective measures [79] of childhood adversity were
short allele of the 5-HTTLPR [37], while the findings from adopted by these studies in comparison to those which
this meta-analysis suggest that the stressful life events found evidence for a gene-environment interaction who
(proximal and provoking factor) significantly interacts mainlyusedquestionnaires(forexample,[74,76]).There
withtheMetvariantofBDNFindepression. are several possible explanations for these null findings.
It has also been postulated that individuals who are The interaction between child adversity and BDNF may
geneticallysensitivitytoadverseexperiences(forexample, be developmentally sensitive and only manifests later in
Metcarriers)maybenefitmostfrompositiveenvironments life (beyond adolescence). It is also possible that the
or even the lack of adversity, under the ‘differentially BDNF-childhood adversity relationship in depression is a
susceptibility’ hypothesis [84]. One study [85] found that measurement artefact. Thus, future studies should assess
the likelihood of experiencing a depressive episode was anadult sampleusing interviewsorobjectivemeasures of
significantly reduced among individuals with at least one childadversity.
Met allele of BDNF but only in the absence of a severe
stressful event. It is possible that interventions that focus Stressfullifeevents
onprovidingsupportiveandpositiveenvironmentswould The results of the meta-analysis showed that the effect
bemostbeneficialtoindividualswhoaregeneticallysensi- of stressful life events on depression is significantly
tivitytostress. moderated by the BDNF polymorphism. The majority
The aetiology of psychiatric disorders such as major of the positive studies measured stressful events using
depression is complex and is likely to involve multiple researcher-administered questionnaires or interviews
interactions between genetic variants and environmental while the majority of the non-replicating studies uti-
factors. Few studies have explored the three-way inter- lised self-report checklists. It is possible that more ob-
action between childhood adversity, stressful life events jective and sensitive approaches to measuring stressful
and stress vulnerability genetic variants [86]. A wealth of life events are required to observe its interaction with
research shows that adversity in childhood sensitises in- BDNFindepression.
dividuals to adult stressful life events increasing their
riskformajordepression[87].Giventhemountingevi- BDNF
dence that genetic variants such as BDNF Val66Met The BDNF gene consists of a number of polymorphisms
polymorphismareimportantstressvulnerabilityfactorssets which may also be relevant for gene-environment inter-
the stage for future studies that should explore the child- actions in depression [55]. The majority of published
hood adversity×stressful life events×BDNF interaction in studies have focused BDNF Val66Met, which allows for
thecontextofdepression. the present meta-analysis, but it would be useful for fu-
ture studies to explore the relationship between other
Childadversity BDNFpolymorphismsandstressindepression.
When examining the specific influence of child adver-
sity, 4 out of 16 studies reported a significant interaction Limitations
with BDNF Val66Met for depression, and 5 were able to Thestudiesreviewedinthisarticlearesubjecttoanumber
providepartialsupportforthisinteraction [65-68].How- of limitations. Firstly, different life stress measures were
ever, the results from the meta-analysis of these studies employed. Questionnaires present the biggest challenge as
providedonlyatrend towards a significanteffect. theyrelyonself-reportandarevulnerabletovariousbiases
On closer inspection of these results it appears that the such as the participant’s subjective interpretation of what
childhood adversity-BDNF relationship in depression may counts as an event and enquire about a restricted number
becomplex,withsomestudiesreportingasignificantinter- of events. Despite these limitations, most studies relied on
actionamongwomenandnotmen[68,73],andforspecific self-report questionnaires, casting doubt on their results.
subtypes ofdepression (non-melancholic) [65].Inaddition, Some studies have attempted to overcome these problems
specific forms of childhood adversity maybe driving these by using trained researchers to administer the question-
associations(forexample,childsexualabuse[66]).Morere- nairesprovidingsomeimprovement.Morerobustmethods,
search in this area is warranted focusing on specific forms such as life stress interviews or use of social services
Hosangetal.BMCMedicine2014,12:7 Page9of11
http://www.biomedcentral.com/1741-7015/12/7
records of child maltreatment are more objective and Authors’contributions
combatmanyofthebiasesassociatedwithself-report. GMHwasresponsiblefordraftingthemanuscriptandcollationofthedata
foranalysis.KETundertooktheanalysesforthestudy,contributedto
Secondly,themajorityofincludedstudiesusedCaucasian
collationandcheckingthedata.CSconductedtheinitialliteraturesearch
samples, which may have influenced the results. It is andcollationofdata.RUandPMcGcontributedtothedesignofthestudy
possible that the BDNF×stress in depression is only andinterpretationoftheresults.Allauthorswereinvolvedindraftingthe
manuscriptandhavegivenfinalapprovaloftheversiontobepublished.
relevant to Caucasian populations, although significant
interactions have been reported among Asian [43] and
ethnically mixed populations [76,77]. Future studies need Acknowledgements
to recruit participants from non-Caucasian backgrounds WewouldliketoexpressourgratitudetoSiobhanLynchforherinputinto
andcommentsonearlydraftsofthismanuscript.WearegratefultoAnnette
totestthe generalisability ofthe BDNF×stressin depres-
LaGreca,BettyLai,KentNilsson,GabriellaJuhasz,MariekeWichers,Joan
siontootherethnicgroups. Kaufman,JustineGatt,AndrewKemp,EstherNederhof,GeorgeBrown,
Thirdly,severalincluded studiesmayhavelimited power LourdesFañanas,MariaClaudiaLattig,Jin-SangYoon,SilviaAlemany,Hans
GrabeandChristianSchwanforprovidingsupplementaryinformationon
due to their restricted sample sizes (for example, [65,78]).
theirstudies.GMHwassupportedbyaMedicalResearchCouncil(MRC)and
For the current study, power analyses revealed that using EconomicSocialResearchCouncil(ESRC)UKInterdisciplinaryPostdoctoral
the pooled samples provided greater than 80% power to Fellowship(PTA-037-27-0165)atthetimeofwritingthepaper.RUissupported
bytheCanadaResearchChairsprogram(http://www.chairs-chaires.gc.ca/
detect significant effects of all three interactions tested in
home-accueil-eng.aspx).Thefundingsourceshadnoroleindesigningthe
this project (these are, (1) life stress×BDNF, (2) child- presentstudy,writingthemanuscriptorthedecisiontosubmit.
hood adversity×BDNF, (3) stressful life events×BDNF
Authordetails
indepression). 1PsychologyDepartment,Goldsmiths,UniversityofLondon,NewCross,
Finally, the statistical approach used to conduct the LondonSE146NW,UK.2MRCSocial,GeneticandDevelopmentalPsychiatry
current meta-analysis relied on combining the P values Centre,InstituteofPsychiatry,King’sCollege,London,DeCrespignyPark,
LondonSE58AF,UK.3King’sCollegeLondon,AcademicCentre,2ndFloor
of existing studies, which were weighted by sample size. HenrietteRaphaelHouse,Guy’sCampus,LondonSE11ULUL,UK.4MRC
This approach was adopted to maximise the number of CentreforNeuropsychiatricGeneticsandGenomics,Departmentof
studies that could be included, with the aim of reducing PsychologicalMedicineandNeurology,SchoolofMedicine,Cardiff
University,CardiffCF244HQ,UK.5DepartmentofPsychiatry,Dalhousie
biases associated with selecting a homogeneous set of University,5909Veterans’MemorialLane,Halifax,NovaScotiaB3H2E2,
studies and to better reflect the current evidence in this Canada.
field. The meta-analytic method of combining P values
Received:26April2013Accepted:24December2013
could be improved upon by using traditional approaches
Published:16January2014
that focus on combining effect sizes, which benefit from
providingthemagnitudeofaneffect.
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