Serotonin transporter polymorphism (5‐HTTLPR) association with melancholic depression: a female specific effect?

Earlier studies yielded inconsistent results on the association between variation in the serotonin transporter (5‐HTT) gene and depression, with evidence for a differential effect of the 5‐HTTLPR on melancholic versus atypical depression. To further delineate the impact of 5‐HTT gene variation on psychopathology in depression, in this analysis the influence of the 5‐HTTLPR and the functionally closely related 5‐HTT rs25531 was investigated in 340 Caucasian patients with a major depressive episode (DSM‐IV) with particular attention to the subtype of depression (melancholic depression versus atypical depression) applying logistic regression models adjusted for age and gender. The homozygous, more active 5‐HTTLPR LL genotype was significantly associated with melancholic depression (odds ratio, OR, 1.7; 95% confidence interval, CI, 1.1–2.6; P=0.04), with the effect originating in the female subgroup of patients (OR 1.9; 95%CI 1.0–3.4; P=0.05). Also, the more active 5‐HTTLPR/5‐HTT rs25531 haplotype LALA conveyed a significant risk for melancholic depression (OR 2.0; 95%CI 1.3–3.1; P=0.001), again only in the female subsample of patients (OR 2.1; 95%CI 1.1–4.1; P=0.02). The present results provide further support for an association of genetic variation increasing serotonin transporter activity with the melancholic subtype of depression as well as evidence for a potential female‐specific mechanism underlying this effect. Depression and Anxiety, 2008. © 2007 Wiley‐Liss, Inc.

[1]  M. Rietschel,et al.  The power of sample size and homogenous sampling: Association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder , 2005, Biological Psychiatry.

[2]  M. Nöthen,et al.  Functional promoter polymorphism of the human serotonin transporter: lack of association with panic disorder. , 1997, Psychiatric genetics.

[3]  C. Benkelfat,et al.  A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders , 2003, Molecular Psychiatry.

[4]  M. Thase,et al.  Gender differences in treatment response to sertraline versus imipramine in chronic depression. , 2000, The American journal of psychiatry.

[5]  D. Murphy,et al.  Isolation of a cDNA encoding the human brain serotonin transporter , 2005, Journal of Neural Transmission / General Section JNT.

[6]  Sylvain Houle,et al.  Novel 5-HTTLPR Allele Associates with Higher Serotonin Transporter Binding in Putamen: A [11C] DASB Positron Emission Tomography Study , 2007, Biological Psychiatry.

[7]  M. Burmeister,et al.  Meta‐analysis of the association between a serotonin transporter promoter polymorphism (5‐HTTLPR) and anxiety‐related personality traits , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[8]  Marcus R. Munafò,et al.  Neuroticism Mediates the Association of the Serotonin Transporter Gene with Lifetime Major Depression , 2006, Neuropsychobiology.

[9]  B. Pollock,et al.  Meta-analysis of serotonin transporter polymorphisms and affective disorders , 2004, Psychiatric genetics.

[10]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[11]  Yasuto Itoyama,et al.  Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety. , 2006, Journal of psychosomatic research.

[12]  Katharina Domschke,et al.  Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. , 2004, The international journal of neuropsychopharmacology.

[13]  P. Blockx,et al.  The decreased availability of L-tryptophan in depressed females: Clinical and biological correlates , 1990, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  P. Sullivan,et al.  Genetic epidemiology of major depression: review and meta-analysis. , 2000, The American journal of psychiatry.

[15]  B. Gutiérrez,et al.  The 5‐HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: The PREDICT‐gene study , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  D. Easton,et al.  Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. , 1998, American journal of medical genetics.

[17]  K. Kendler,et al.  Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? , 2001, Psychological Medicine.

[18]  S. Faraone,et al.  Meta‐analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[19]  R. Murray,et al.  A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. , 1996, Molecular psychiatry.

[20]  M. Nöthen,et al.  Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. , 1999, Human molecular genetics.

[21]  M. Weissman,et al.  Cross-national epidemiology of major depression and bipolar disorder. , 1996, JAMA.

[22]  J. Thome,et al.  Promoter polymorphism of the 5-HT transporter and Alzheimer's disease , 2000, Neuroscience Letters.

[23]  C. Nemeroff,et al.  Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. , 1994, Clinical chemistry.

[24]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[25]  D Winkler,et al.  A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder , 2003, Molecular Psychiatry.

[26]  D. Williams,et al.  The serotonin transporter: a primary target for antidepressant drugs , 1998, Journal of psychopharmacology.

[27]  H. Tanabe,et al.  The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants , 2000, Molecular Psychiatry.

[28]  M. Munafo,et al.  The Serotonin Transporter Length Polymorphism, Neuroticism, and Depression: A Comprehensive Assessment of Association , 2005, Biological Psychiatry.

[29]  D. Silberberg,et al.  Radioimmunoassay for detection of anti-oligodendrocyte antibodies , 1981, Neuroscience Letters.

[30]  M. Leboyer,et al.  Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression , 1998, Neuroscience Letters.

[31]  F. Mayoral,et al.  The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort , 2007, Molecular Psychiatry.

[32]  D. Murphy,et al.  Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531 , 2006, Molecular Psychiatry.

[33]  F. Martényi,et al.  Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile , 2001, European Neuropsychopharmacology.

[34]  J. van os,et al.  Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. , 2006, Archives of general psychiatry.

[35]  L. Bierut,et al.  Major depressive disorder in a community-based twin sample: are there different genetic and environmental contributions for men and women? , 1999, Archives of general psychiatry.