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Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden

Molecular Psychiatry volume 16, pages 354–356 (2011)Cite this article

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There is a controversial and ongoing debate on whether mental distress is moderated by an interaction between the insertion or deletion promoter polymorphism of the serotonin transporter gene (5-HTTLPR) and life adversities. In particular, two meta-analyses published in 2009, which were based on a selection of 5 and 14 studies (from 34 observational studies in total), respectively, concluded that there is insufficient evidence for the existence of an interaction between 5-HTTLPR and stressful life events in depression.1, 2 However, the methodology of these two meta-analyses has raised concerns, as important methodological differences between the individual studies were disregarded.3, 4 Nevertheless, the high methodological quality of each individual study contributing to this field is of utmost importance. The paper of Grabe et al.5 published in 2005 was one of the first on this topic after the initial report by Caspi et al.6 Since then, our paper has been cited over 100 times and has been included in all meta-analyses on this topic. Our original analysis was performed in a subset of 977 individuals, who were non-randomly selected from the population-based sample of the Study of Health in Pomerania (SHIP).7 The finding of a gene–environment interaction was based on a three-way interaction between ‘number of chronic diseases’, unemployment, and the S versus L allele carrier status (SS and SL versus LL). The interaction was significant (P<0.001) in the sample of 977 subjects, but it was driven by the female group only. In separate two-way interactions, no significant results emerged. However, three-way interactions may be prone to false-positive findings because of low numbers of subjects in the high-exposure group. We therefore updated the former analyses using the total representative SHIP sample (n=4308).7 Further, we were interested in gender effects, in the effect of an additional functional A/G-polymorphism (rs25531) within the promoter region and in the identification of the risk allele, as some studies found the L-allele to be associated with the risk for depression.8, 9 The 5-HTTLPR and rs25531 polymorphisms were genotyped according to Grabe et al.10 and identical statistical methods and definitions of stressors and outcomes were applied as in the initial report.5 Besides unemployment as a putative stressor, the interview-rated number of chronic diseases (myocardial infarction, stroke, diabetes, kidney disease, chronic bronchitis, arthritis and degenerative diseases of the joints and spine, osteoporosis, peptic ulcer, pancreatitis, gastrointestinal bleedings, migraine, thyroid disease, cancer, multiple sclerosis, and Parkinson's disease) was taken as another stressor. The modified version of von Zerssen's complaints scale was used to assess psychological and somatic symptoms and complaints by self-report on 38 items.5 Complete genotype and clinical data were available for n=4000 subjects (2022 females). Missing values occurred mainly because of employment status, whereas the genotype rate was >98% (n=4262). The analyses were adjusted for gender and age. As social support did not change the interaction coefficients >10%, it was not included in the final models because of 112 missing observations for this variable. We analyzed the ‘bi-allelic’ genotype in a dichotomized (SS and SL versus LL) and additive allelic model and the so-called ‘tri-allelic’ genotype, including rs25531. Following previous reports on gene expression, we classified the genotypes into three functional ‘tri-allelic’ genotypes: LA/LA, LG/LA or S/LA, LG/LG or LG/S or S/S, which were grouped into LA/LA versus all other genotypes for the dichotomized model.

Figure 1 shows a switch in the risk allele in the highest-exposure group (⩾4 chronic diseases). This switch was statistically significant (comparison between 3 versus ⩾4 chronic diseases; P=0.001).

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Acknowledgements

We have received the following external financial support during the past 5 years: Hans Joergen Grabe: German Research Foundation; Federal Ministry of Education and Research Germany; speaker's honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, Servier, and travel funds from Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. Carsten Spitzer: travel funds and speaker's honoraria from Janssen-Cilag and Boehringer Ingelheim; research grant from the ‘Stiftung zur Aufarbeitung der SED-Diktatur.’ Sven Barnow: German Research Foundation; Federal Ministry of Health Germany. Harald J. Freyberger: German Research Foundation; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Family Ministry of the Federal Republic of Germany; speaker's honoraria from AstraZeneca, Lilly, Novartis and travel funds from Janssen-Cilag. Ulrich John: German Research Foundation; German Cancer Aid; European Union; Federal Ministry of Education and Research Germany; Social Ministry of the Federal State of Mecklenburg-West Pomerania of Germany. Dieter Rosskopf: Federal Ministry of Education and Research Germany, Alfried Krupp von Bohlen und Halbach Foundation; speaker's honoraria from Novartis and Essex Pharma. Henry Völzke: research grants by Sanofi-Aventis, Biotronik, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany) and the German Research Foundation.

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  1. H J Grabe and C Schwahn: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Greifswald, Greifswald, Germany

    H J Grabe, K Appel, J Mahler, A Schulz & H J Freyberger

  2. Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Greifswald, Germany

    C Schwahn

  3. Department of Psychosomatic Medicine and Psychotherapy, University of Hamburg, Hamburg, Germany

    C Spitzer

  4. Institute of Clinical Psychology, University of Heidelberg, Hamburg, Germany

    S Barnow

  5. Institute of Epidemiology and Social Medicine, University of Greifswald, Greifswald, Germany

    U John

  6. Institute of Pharmacology, University of Greifswald, Greifswald, Germany

    D Rosskopf

  7. Institute for Community Medicine, University of Greifswald, Greifswald, Germany

    H Völzke

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Grabe, H., Schwahn, C., Appel, K. et al. Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden. Mol Psychiatry 16, 354–356 (2011). https://doi.org/10.1038/mp.2010.45

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