TABLE 1.

Human Observational Studies Testing the Hypothesis That the 5-HTTLPR Moderates the Effect of Stress on Depression Phenotypes in Studies of Specific Stressors

Specific Stressor and Studya	Designb	N	Female (%)	Mean Age	Location	Stress Assessment	Stressor	Outcome Measurec	G×E Interactiond
Childhood maltreatment
Caspi (2003) [R, M]	Longitudinal	847	50	26	New Zealand	Objective/interview	Child maltreatment	Diagnosis of depression	Yes: additive
Kaufman (2004/2006)e	Cross-sectional	196	51	9	U.S.	Objective	Child abuse	MFQ	Yes: recessive
Cicchetti (2007)	Cross-sectional	339	47	17	U.S.	Objective	Child abuse	Anxious/depressed symptoms (ASEBA)	Yes (sexual abuse): recessive
Wichers (2008)	Cross-sectional	394	100	18–64 years	Belgium	Questionnaire	Childhood Trauma Questionnaire (items concerning sexual and physical abuse were omitted)	SCL-90; SCID depressive symptoms	No (3-way interaction between 5-HTTLPR S carriage, BDNF Met carriage, and childhood maltreatment)
Aguilera (2009)	Cross-sectional	534	55	23	Spain	Questionnaire	Childhood Trauma Questionnaire	SCL-90-R	Yes (sexual abuse): dominant
Aslund (2009)	Cross-sectional	1,482	48	17–18 years	Sweden	Questionnaire	Quarrels between parents; violence between parents; physical maltreatment; psychological maltreatment.	Depression Self-Rating Scale	Yes (females): additive
Benjet (2010)	Cross-sectional	78	100	10 to 14 years	U.S.	Questionnaire	Victims of relational aggression	Children’s Depression Inventory	Yes: recessive
Kumsta (in press)	Longitudinal	125	NA	Assessed at ages 11 and 15 years	England	Objective	Institution rearing between 6–42 months in Romanian orphanages	Depressive symptoms (CAPA, Rutter Child Scale; Strengths & Difficulties Questionnaire)	Yes: additive
Sugden (in press)	Longitudinal	2,017	51	12	England	Interview	Victims of bullying	Anxious/depressed symptoms (ASEBA)	Yes: additive
Medical conditionsf
Mossner (2001)	Exposed Only	72	46	NA	Germany	Objective	Patients with idiopathic Parkinson’s disease	Hamilton Rating Scale for Depression	Yes: additive
Grabe (2005) [R]g	Cross-sectional	976	60	52	Germany	Questionnaire	Number of chronic diseases	von Zerssen’s Complaints Scale (psychological and somatic symptoms)	Yes (females): dominant
Lenze (2005)	Exposed only	23	87	77	U.S.	Objective	Rehabilitation-hospital patients with hip fracture	Diagnosis of depression	Yes: dominant
Nakatani (2005)	Exposed only	2,509	25	64	Japan	Objective	Patients with acute myocardial infarction	Zung Self-rating Depression Scale	Yes: dominant
Ramasubbu (2006)	Exposed only	51	NA	60	Canada	Objective	Stroke survivors	Diagnosis of depression	Yes: dominant
Otte (2007)	Exposed only	557	15	68	U.S.	Objective	Patients with documented coronary disease	Diagnosis of depression	Yes: dominant
Kohen (2008)	Exposed only	150	37	60	U.S.	Objective	Stroke survivors	Geriatric Depression Scale	Yes: recessive
McCaffery (2008)	Exposed only	977	21	59	Canada	Objective	Patients with established cardiovascular disease	BDI	No
Kim (2009)	Longitudinal	521	55	72	Korea	Questionnaire	Number of chronic health problems	Diagnosis of depression	Yes: recessive
Other stressors
Kilpatrick (2007)	Cross-sectional	589	64–77	> 60	U.S.	Objective/questionnaire	Hurricane exposure + low social support 6 months before the hurricane	Diagnosis of depression	Yes: additive
Brummet (2008)	Cross-sectional	288	75	58	U.S.	Objective	Caregivers of patients with Alzheimer’s disease/dementia	CES-D	Yes (females): additive

^aFull references are available in a data supplement that accompanies the online version of this article. Studies included in the Risch et al. meta-analysis are marked with an [R]; studies included in the Munafo et al. meta-analysis are marked with an [M].

^bCase only designs studied depressed patients, and the parameter of interest was whether genotype distinguished cases who had the environmental exposure. Case-control designs compared depressed patients and healthy subjects on genetic and environmental risk factors. Cross-sectional designs studied the association between genetic and environmental factors and depression phenotypes at a point time. All three designs are prone to bias because information about the exposure is assessed retrospectively. Information bias can be minimized by careful instrument construction, by seeking an objective record of the exposure, or by obtaining information about the exposure and the outcome from independent sources. Longitudinal designs usually assess the environmental exposure before the outcome, thereby minimizing some biases. However, many G×E studies that have been carried out in the context of prospective longitudinal studies have collected exposure information retrospectively at the same time as collecting outcome information, thereby undermining the strength of the design. Exposed-only designs studied individuals selected on the basis of their environmental exposure, and the parameter of interest was whether genotype was associated with depression outcome.

^cBDI: Beck Depression Inventory; CES-D: Center for Epidemiologic Studies Depression Scale; MFQ: Mood & Feelings Questionnaire; ASEBA: Achenbach System of Empirically Based Assessment; SCL-90: Symptom Checklist; CAPA: Child and Adolescent Psychiatric Assessment.

^dInformation in parentheses indicates whether the interaction was conditional (e.g., for one sex only, for a specific measure, etc.). Genetic models are generally not systematically compared in the reports and our rating is based on having read the method and results sections of each paper.

^eThe initial report contained 101 children. The second report contained 196 children, including those in the original report.

^fA consideration in studies of depression-inducing medical illnesses is whether these illnesses index “psychological stress” or an independent biological mechanism that is part and parcel of the medical illness. The latter possibility is suggested by evidence that depression is linked to abnormalities in endogenous cytokines and that stimulating proinflammatory cytokines induces depression, especially among 5-HTTLPR S-carriers (in some [Bull, 2008; Lotrich, 2009] but not all [Kraus, 2007] studies). Because the etiology of depression following medical illness is multifactorial, involving both psychological and biological mechanisms, it is not yet possible to tell what part of the “stress of being ill” is moderated by the 5-HTTLPR in these studies.

^gThis report also analyzed unemployment as a stressor and found that unemployed S carriers reported more psychological and somatic symptoms. This interaction was observed among females, but not among males.