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From JAMA |

Gene-Environment Interactions Biologically Valid Pathway or Artifact?

Michael Rutter, MD, FRCPsych, FRS; Anita Thapar, PhD, FRCPsych; Andrew Pickles, PhD
Arch Gen Psychiatry. 2009;66(12):1287-1289. doi:10.1001/archgenpsychiatry.2009.167.
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Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

Neil Risch, PhD; Richard Herrell, PhD; Thomas Lehner, PhD; Kung-Yee Liang, PhD; Lindon Eaves, PhD; Josephine Hoh, PhD; Andrea Griem, BS; Marika Kovacs, PhD; Jurg Ott, PhD; Kathleen Ries Merikangas, PhD

Context:   Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression.

Objective:   To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data.

Data Sources:   Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis.

Study Selection:   Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data.

Data Extraction:   Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14 250 participants, 1769 were classified as having depression; 12 481 as not having depression.

Results:   In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data.

Conclusion:   This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

JAMA. 2009;301(23):2462-2471..


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The Role of Epigenetics in Gene-Environment Interactions
Posted on January 24, 2010
Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, India
Conflict of Interest: None Declared
In a thought-provoking commentary, Rutter et al(1) discussed the role of gene-environment (GXE) interactions in the field of psychopathology, with special reference to the meta-analysis of Risch et al(2) which found no evidence that the serotonin transporter (5-HTT) genotype, alone or in interaction with stressful life events, is associated with an elevated risk of major depression. Rutter et al cited evidence supporting the opinion that GXE interactions are to be expected in psychopathology, and alluded to the view that GXE interactions could have implications for statistical analysis and health care. They also suggested that the Risch et al(2) article was seriously flawed in casting doubt on all GXE findings on the 5-HTT gene. In this context, I wish to discuss the role of epigenetics (heritable changes in gene expression not involving changes in DNA sequence) in GXE interactions. Epigenetics involves a number of molecular mechanisms like DNA methylation, histone modification, small RNA-mediated regulation of gene expression, and chromatin remodelling(3) and there is increasing evidence that it plays a major role in the pathogenesis of mental disorders.(4) Environmental factors are known to alter epigenetic mechanisms and there is evidence that epigenetics is an interface between the environment and genes in the pathogenesis of mental disorders.(4) A possible reason for the inconsistent results for the role of the 5-HTT gene in major depression as found by Risch et al(2) is that this gene is epigenetically modified in patients with this disorder. This suggestion is supported by the finding that in lymphoblast cell lines the methylation status of the 5-HTT gene was associated with levels of 5-HTT messenger RNA5 and the preliminary finding that this gene is abnormally methylated in patients with major depression.(6) In the light of the above, epigenetics may require due attention in studies on GXE interactions involving the 5-HTT gene in major depression and in similar studies involving other genes and other areas of psychopathology.
Conflicts of Interest: None
1. Rutter M, Thapar A, Pickles A. Gene-environment interactions. Biologically valid pathway or artifact? Arch Gen Psychiatry 2009; 66 (12): 1287-1289.
2. Risch N, Herrell R, Lehner T, Liang K-Y, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009; 301(23) 2462 – 2471.
3. Allis CD, Jenuwein T, Reinberg D. Overview and concepts. In: Epigenetics, (eds): Allis CD, Jenuwein T, Reinberg D. New York: Cold Spring Harbor Laboratory Press,2007, 23-61.
4. Peedicayil J. The role of epigenetics in mental disorders. Indian J Med Res 2007; 126(2): 105-111.
5. Philibert R, Madan A, Andersen A, Cadoret R, Packer H, Sandhu H. Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island. Am J Med Genet B Neuropsychiatr Genet 2007; 144B (1): 101-105.
6. Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa adoption studies. Am J Med Genet B Neuropsychiatr Genet 2008; 147B (5): 543-549.
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