TABLE 2.

Human Observational Studies Testing the Hypothesis That the 5-HTTLPR Moderates the Effect of Stress on Depression Phenotypes in Studies of Stressful/Adverse Life Events

Studya	Designb	N	Female (%)	Mean Age	Location	Stress Assessment	Stressor	Outcome Measurec	G×E Interactiond
Caspi (2003) [R, M]	Longitudinal	845	50	26	New Zealand	Interview	Past 5 years	Diagnosis of depression	Yes: additive
Eley (2004) [R, M]	Case-Control	377	58	12–19 years	England	Questionnaire	Family environmental risk assessed with three variables: The Social Problems Questionnaire, parental education, and adverse life events.	MFQ	Yes (females):additive
Kendler (2005)	Longitudinal	572	NA	35	U.S.	Interview	Nearest month of stressful life events	Diagnosis of depression	Yes: recessive
Jacobs (2006)	Longitudinal	374	100	27	Holland	Questionnaire	Past 3 months	SCL-90	Yes: additive
Mandelli (2006)	Case only	670	68	48	Italy	Interview	12 months preceding onset of first depression	Diagnosis of depression	Yes: dominant
Taylor (2006) [R]	Cross-sectional	118	57	21	U.S.	Questionnaire	Adverse childhood experiences/past 6 months	BDI	Yes: recessive
Sjoberg (2006)	Cross-sectional	180	63	16–19 years	Sweden	Interview	Lifetime: 6 questions about psychosocial circumstances in the family	Depression Self-Rating Scale	Yes (females): additive
Wilhelm (2006) [R]	Longitudinal	127	67	48	Australia	Interview	1 year and 5 years prior to depression	Diagnosis of depression	Yes (for events in past five years): additive
Zalsman (2006)	Case-control	316	68	38	U.S.	Interview	Past 6 months	Hamilton Depression Rating Scale	Yes: dominant
Cervilla (2007) [R]	Case-control	737	72	49	Spain	Questionnaire	Past 6 months	Diagnosis of depression	Yes: recessive
Dick (2007)	Family-based association study	1,913	NA	NA	U.S.	Questionnaire	Unemployment in past 12 months; divorced, widowed or separated; and reporting fair or poor health	Diagnosis of depression	Yes, family-based analyses, over-transmission of the short allele concentrated among individuals who experienced stressful life events
Kim (2007) [R, M]	Cross-sectional	732	NA	65+	Korea	Interview	Past 12 months	Diagnosis of depression	Yes: dominant
Scheid (2007) [M]	Cross-sectional	495 pregnant woman	100	20–34 (81%)	U.S.	Questionnaire	Lifetime events, grouped by type	CES-D	Yes (abuse, but not other stressful life events): recessive
Lazary (2008)	Cross-sectional	567	79	31	Hungary	Questionnaire	Past 2 years	Zung Self-Rating Depression Scale	Yes: additive
Bukh (2009)	Case only	290	66	39	Denmark	Interview	6-months preceding onset of the patients’ first episode of depression	Diagnosis of depression	Yes: recessive
Goldman (in press)	Longitudinal	984	45	66	Taiwan	Interview	Lifetime	CES-D	Yes: additive (extended to include the XL genotype)
Gillespie (2005) [R]	Cross-sectional	1,091	NA	39	Australia	Questionnaire	Past 12 months	Diagnosis of depression	No
Surtees (2006) [R, M]	Cross-sectional; selected for high and low extreme Neuroticism scores	4,175	47	60	England	Questionnaire	Childhood adverse experiences/Up to 6 stressful life events in 5 past years	Diagnosis of depression	Opposite (childhood adverse experiences); Negative (adult life events)
Chipman (2007) [R]	Cross-sectional	2,095	52	20–24	Australia	Questionnaire	Past 6 months	Goldman Depression Scale	No
Chorbov (2007) [R]	Longitudinal	236	100	22	U.S.	Questionnaire	History of traumatic events	Diagnosis of depression	Opposite
Araya (2009)	Longitudinal	4,334	NA	7	England	Questionnaire	Past 2 years (list of events that children found upsetting, according to maternal checklist)	SDQ emotional symptom 5-item subscale	No
Laucht (2009) [R]	Cross-sectional	309	54	19	Germany	Questionnaire	Past 5 years	Diagnosis of depression; BDI	No
Power (2009) [R]	Cross-sectional	1,421	NA	65+	France	Questionnaire	Past 12 months	Case-level depression, according to MINI and CES-D	No
Zhang (2009)	Case-control	792	54	33	China	Questionnaire	Negative life events (in family life, working problems, and social life)	Diagnosis of depression	Opposite

^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]. A study by Middeldorp et al. was included in the meta-analysis by Risch et al. although no test of gene-environment interaction was reported in available publications.

^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.

^cBDI: Beck Depression Inventory; CES-D: Center for Epidemiologic Studies Depression Scale; MFQ: Mood & Feelings Questionnaire; SCL-90: Symptom Checklist; MINI: Mini International Neuropsychiatric Interview; SDQ: Strengths and Difficulties Questionnaire.

^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.