Stressful life events, 5-HTT genotype and risk of depression

Studies of how genetic and environmental exposures interactmay be essential for understanding the aetiology of complexpsychiatric disorders. In this issue of the Journal an Australianstudy reports evidence of such an interaction on risk of depression.We discuss findings in this field in the context of the limitationsinherent in studies of gene–environment interactions.

INTRODUCTION

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INTRODUCTION

The processes underlying psychiatric disease are clearly extremelycomplex. Studies of how genes and environment interact andaffect vulnerability to risk of disease are likely to contributesubstantially to our understanding of these processes. Thestudy by Wilhelm et al (2006, this issue) adds to a growingbody of literature suggesting that the effects of stressfullife events on risk of depression may be dependent on variationat the 5-HTTLPR locus of the serotonin transporter (5-HTT)gene. The study of gene–environment interactions, althoughclearly important, is beset with a number of potential problems,and we discuss these findings within this context.

GENE–ENVIRONMENT INTERACTIONS

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GENE-ENVIRONMENT INTERACTIONS

A situation where risk from an environmental exposure variesaccording to genotype or where genotype effect varies accordingto environment is known as gene–environment interaction,or effect modification. Studies of genetic effects stratifiedby environmental exposures, or vice versa, may increase our ability to find evidence of risk or protective factors fordisease, and increase understanding of pathophysiology. Theymay also allow more accurate estimation of effect sizes withinpopulation subgroups, and–although difficulties in implementingchange in high-risk groups are substantial–may allowfor specific targeting of interventions in the future.

Studies of interactions need to be approached with caution fora number of reasons. First, sub-analyses inevitably resultin more statistical tests and consequently increased likelihoodof type I errors. Second, the smaller numbers of events withincomparison groups lead to reduced statistical power, whichwill only be offset in the presence of a strong interactioneffect. Third, evidence for statistical interaction does notprovide direct evidence of biological interaction. Evidenceof statistical interaction depends on the mathematical modelused and, as the null hypothesis is that joint exposure effectson outcome are as described by the model, rejecting this hypothesis has less clear biological meaning than for the study of maineffects (Clayton & McKeigue, 2001).

5-HTT, STRESSFUL LIFE EVENTS AND DEPRESSION

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5-HTT, STRESSFUL LIFE EVENTS...

Evidence for an interaction between 5-HTTLPR genotype and adultdepression was first reported in the Dunedin birth cohort (Caspi et al, 2003).Presence of the short (‘s’) alleleof 5-HTTLPR reduces in vitro gene transcription and transporteractivity compared with the long (‘l’) allele, resultingin increased synaptic levels of serotonin. In this study, presenceof stressful life events was associated with an increase inrisk of depression in heterozygous individuals and in those homozygous for the ‘s’ allele, but not in ‘l/l’ homozygotes. Five studies have since reported similar deleteriouseffects of adverse events on depression, modified by the underlyinggenotype at this locus (studies 2–6 in Table 1). Inthese studies the interaction effect was in the same directionas the original finding, although it was only observed in womenin two of the studies. Some of these results, however, aredifficult to explain biologically. For example, Sjoberg etal (2005) reported interactions between 5-HTTLPR genotypeand various adversity measures on risk of depression, but theinteraction effects observed were in opposite directions inmen and women. Although gender-specific effects are compatiblewith some observations from animal models, opposite effectsof genetic modification of stress on depression risk betweengenders seems biologically less plausible.

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Table 1 Summary of studies examining the relationship between serotonin transporter (5-HTT) genotype, stressful life events and depression

In this issue Wilhelm et al report an interaction between genotype and stressful life events on risk of depression, with increasedrisk present in ‘s/s and ‘s/l’ but not ‘l/l’phenotypes (Wilhelm et al, 2006, this issue). Adverse eventsappear to protect against depression in the ‘l/l’group, although it is not clear whether the confidence intervalshere are compatible with a null effect. Interestingly, a similar trend is observed in other studies that have reported an interaction,although an opposite effect of adversity on depression riskacross genotypes seems biologically unlikely.

SUPPORTING EVIDENCE

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SUPPORTING EVIDENCE

In rhesus macaques interactions between rearing experience andrh5-HTTLPR (analogous to the human polymorphism) have beendescribed for a number of potential depression-related outcomes(Barr et al, 2003). These findings probably require further replication, and lack of a clear pattern in the interactionsreported for adrenocorticotrophic hormone and cortisol responseto stress complicates interpretation of some results. Nevertheless,these studies provide a fascinating insight into possible advancesto be gained from future research in this field. Other supportfor effect modification of stress by 5-HTT genotype comes fromneuroimaging studies, where amygdala hyperreactivity in responseto fearful stimuli has been reported in individuals with ‘s’alleles compared with ‘l/l’ homozygous individuals in a number of studies (for example, see Hariri et al, 2005).

EVIDENCE AGAINST

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EVIDENCE AGAINST

Surtees et al (2005), in the largest and most high-poweredstudy to date examining this relationship, found no evidence of an interaction between genotype and adverse experiencesin childhood or adulthood on risk of depression. In men, aninteraction was observed for childhood adversity, but thiswas in the opposite direction to that reported by Caspi etal (2003). Another study, by Gillespie et al (2005), alsofailed to find evidence of interaction. Moreover, a non-significanttrend for increased depression in ‘l/l’ homozygousindividuals who had experienced more stressful life eventswas again in the opposite direction to the findings reportedby Caspi and colleagues.

WEIGHING UP THE EVIDENCE

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WEIGHING UP THE EVIDENCE

Although the studies to date have examined different depressionand environmental stress measures, and employed different studydesigns and genetic models, most find evidence for a gene–environmentinteraction from both multiplicative as well as linear statisticalmodels. However, the two largest studies to date find no evidenceto support such an interaction, although issues regarding studydesign as well as temporal sequence and validity of measuresare also important to consider when summarising findings acrossstudies. Nevertheless, studies of interactions tend to be relatively low-powered, and as initial findings tend, on average, to beoverestimates of true effect sizes, larger samples than thoseused in the original study are usually required for replication.Given that there is evidence of interaction from a number ofstudies with fairly small sample sizes, but no small negative studies, as can be seen in Table 1, it seems likely that publicationbias is occurring, making interpretation of the evidence moreproblematic.

FUTURE DIRECTIONS

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FUTURE DIRECTIONS

In view of the above we believe it is sensible to be cautiousin the interpretation of results from these studies. The consistencyof findings from animal studies with these epidemiologicalobservations suggests that the effects of stressful eventsmight indeed be mediated by 5-HTTLPR genotype. If this canbe confirmed by further adequately powered and well-designedstudies, this will provide an intriguing base for further explorationand dissection of pathological mechanisms underlying depression.Guidelines for the study of gene–environment interactionssuggest useful strategies as to how future studies may bestbe approached (Moffitt et al, 2005). Studies such as thosediscussed here and those reporting evidence for gene–environmentinteraction in other psychiatric disorders (Caspi et al, 2002, 2005) have all focused on reasonably well-supported candidategenes and environmental factors. Independent effects for mostof these exposures are already established, and it is not yetclear to what extent these sorts of findings will influenceour understanding of pathophysiology.

Interestingly, for most of these studies, a clear effect ofgenotype was only observed after stratification by environmentalexposure, and recent meta-analyses provide only weak evidence,if any, of association between 5-HTTLPR and depression (Levinson, 2005).Consequently, it has been suggested that genome-widescans for novel genes might profitably be based upon affectedand unaffected samples selected for known exposure to an environmentalpathogen for the disorder (Moffitt et al, 2005). This hasinherent attractions where robust effects of specific environmentaleffects have been demonstrated. However, there are limitations.First, the number of environmental pathogens that have been clearly implicated in psychiatric disorders is small; it seemsunlikely that the majority of risk genes for psychiatric disorderswill interact with these few well-established pathogens, andthe scope of such studies will thus be limited. Second, theunit costs of studies that include measurements of environmentalexposures of sufficient quality will be great. Even though there should be gains in power to detect genes interacting with thecandidate environmental exposure, it is not clear whether thesewill outweigh the increased cost per sample compared with necessarilylarger studies of cases unselected for environmental exposure,where the unit costs are much lower. Population-based longitudinalstudies that have both DNA as well as detailed environmentalexposure data throughout the life course are ideally placedfor such studies, and greatly improve the economic case forgenetic studies of environmentally stratified samples.

The study of how genetic and environmental exposures interacton risk of disease may be an essential element to understandingcomplex disorders. However, the study of interactions requiresa more cautious approach than studies of main effects, andevidence for modification of the effects of stress on riskof depression by 5-HTTLPR genotype is not yet robust. Although heralding much promise, the extent to which this fascinatingarea of research will enhance our understanding of psychiatricdisease remains to be seen.

REFERENCES

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