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Meta-Analysis
, 23 (1), 133-142

Collaborative Meta-Analysis Finds No Evidence of a Strong Interaction Between Stress and 5-HTTLPR Genotype Contributing to the Development of Depression

R C Culverhouse  1 N L Saccone  2 A C Horton  3 Y Ma  3 K J Anstey  4 T Banaschewski  5 M Burmeister  6   7 S Cohen-Woods  8 B Etain  9   10   11 H L Fisher  12 N Goldman  13 S Guillaume  14   15   16 J Horwood  17 G Juhasz  18   19   20   21 K J Lester  22 L Mandelli  23 C M Middeldorp  24   25 E Olié  14   15   16 S Villafuerte  6 T M Air  26 R Araya  27 L Bowes  28 R Burns  4 E M Byrne  29 C Coffey  30 W L Coventry  31 K A B Gawronski  32 D Glei  33 A Hatzimanolis  34   35 J-J Hottenga  24   36 I Jaussent  15 C Jawahar  26 C Jennen-Steinmetz  37 J R Kramer  38 M Lajnef  39 K Little  40   41 H M Zu Schwabedissen  42 M Nauck  43 E Nederhof  44 P Petschner  19   21   45 W J Peyrot  46 C Schwahn  47 G Sinnamon  26 D Stacey  26 Y Tian  48 C Toben  26 S Van der Auwera  49 N Wainwright  50 J-C Wang  51 G Willemsen  24   36 I M Anderson  20   52 V Arolt  53 C Åslund  54   55 G Bagdy  19   21   45 B T Baune  26 F Bellivier  9   10   11 D I Boomsma  24   25   36 P Courtet  14   15   16 U Dannlowski  53 E J C de Geus  24   36 J F W Deakin  20   52 S Easteal  56 T Eley  57 D M Fergusson  17 A M Goate  51 X Gonda  19   21   45   58 H J Grabe  49 C Holzman  48 E O Johnson  59 M Kennedy  60 M Laucht  5 N G Martin  61 M R Munafò  62   63 K W Nilsson  54   55 A J Oldehinkel  44 C A Olsson  64   41   30 J Ormel  44 C Otte  65 G C Patton  66 B W J H Penninx  46 K Ritchie  15 M Sarchiapone  67 J M Scheid  68 A Serretti  23 J H Smit  46 N C Stefanis  34   35 P G Surtees  50 H Völzke  69 M Weinstein  33 M Whooley  70 J I Nurnberger Jr  71 N Breslau  48 L J Bierut  3
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Meta-Analysis

Collaborative Meta-Analysis Finds No Evidence of a Strong Interaction Between Stress and 5-HTTLPR Genotype Contributing to the Development of Depression

R C Culverhouse et al. Mol Psychiatry.

Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Figures

Figure 1
Figure 1
Forest plots for lifetime depression diagnosis in subjects of all ages based on exposure to childhood maltreatment as the stressor MODEL:depression=β0+β1(age)+β2(sex)+β3(stress)+β4(gene)+β5(gene×stress)Depression = lifetime depression diagnosis (never depressed = 0; ever depressed = 1) Sex (female = 0; male = 1) Stress = childhood maltreatment (not exposed = 0; exposed = 1) Gene (additive coding in number of S alleles for 5-HTTLPR (LL = 0; LS=1; SS=2)) 1a. Sex: Being male consistently and significantly protects from a lifetime diagnosis of depression 1b. Stress: Exposure to stress consistently and significantly increases lifetime risk for depression 1c. Gene: The S allele (coded additively) is not associated with risk of lifetime depression 1d. Gene x Stress: Interaction term is not significant and does not suggest a consistent direction of effect across studies. (Hypothesized direction of effect: OR > 1)
Figure 1
Figure 1
Forest plots for lifetime depression diagnosis in subjects of all ages based on exposure to childhood maltreatment as the stressor MODEL:depression=β0+β1(age)+β2(sex)+β3(stress)+β4(gene)+β5(gene×stress)Depression = lifetime depression diagnosis (never depressed = 0; ever depressed = 1) Sex (female = 0; male = 1) Stress = childhood maltreatment (not exposed = 0; exposed = 1) Gene (additive coding in number of S alleles for 5-HTTLPR (LL = 0; LS=1; SS=2)) 1a. Sex: Being male consistently and significantly protects from a lifetime diagnosis of depression 1b. Stress: Exposure to stress consistently and significantly increases lifetime risk for depression 1c. Gene: The S allele (coded additively) is not associated with risk of lifetime depression 1d. Gene x Stress: Interaction term is not significant and does not suggest a consistent direction of effect across studies. (Hypothesized direction of effect: OR > 1)
Figure 1
Figure 1
Forest plots for lifetime depression diagnosis in subjects of all ages based on exposure to childhood maltreatment as the stressor MODEL:depression=β0+β1(age)+β2(sex)+β3(stress)+β4(gene)+β5(gene×stress)Depression = lifetime depression diagnosis (never depressed = 0; ever depressed = 1) Sex (female = 0; male = 1) Stress = childhood maltreatment (not exposed = 0; exposed = 1) Gene (additive coding in number of S alleles for 5-HTTLPR (LL = 0; LS=1; SS=2)) 1a. Sex: Being male consistently and significantly protects from a lifetime diagnosis of depression 1b. Stress: Exposure to stress consistently and significantly increases lifetime risk for depression 1c. Gene: The S allele (coded additively) is not associated with risk of lifetime depression 1d. Gene x Stress: Interaction term is not significant and does not suggest a consistent direction of effect across studies. (Hypothesized direction of effect: OR > 1)
Figure 1
Figure 1
Forest plots for lifetime depression diagnosis in subjects of all ages based on exposure to childhood maltreatment as the stressor MODEL:depression=β0+β1(age)+β2(sex)+β3(stress)+β4(gene)+β5(gene×stress)Depression = lifetime depression diagnosis (never depressed = 0; ever depressed = 1) Sex (female = 0; male = 1) Stress = childhood maltreatment (not exposed = 0; exposed = 1) Gene (additive coding in number of S alleles for 5-HTTLPR (LL = 0; LS=1; SS=2)) 1a. Sex: Being male consistently and significantly protects from a lifetime diagnosis of depression 1b. Stress: Exposure to stress consistently and significantly increases lifetime risk for depression 1c. Gene: The S allele (coded additively) is not associated with risk of lifetime depression 1d. Gene x Stress: Interaction term is not significant and does not suggest a consistent direction of effect across studies. (Hypothesized direction of effect: OR > 1)

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References

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