Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors.
BACKGROUND
Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.


METHODS
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.


RESULTS
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.


CONCLUSIONS
Our study is cross-sectional and applies self-report questionnaires.


CONCLUSIONS
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Gabriella
G
Juhasz
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary.
Xenia
X
Gonda
MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary.
Gabor
G
Hullam
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Nora
N
Eszlari
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
David
D
Kovacs
Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary.
Judit
J
Lazary
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Dorottya
D
Pap
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Peter
P
Petschner
Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Rebecca
R
Elliott
Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
John Francis William
JF
Deakin
Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom, and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Ian Muir
IM
Anderson
MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary.
Peter
P
Antal
Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany, and Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands.
Klaus-Peter
KP
Lesch
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Gyorgy
G
Bagdy
D000328:Adult; D000367:Age Factors; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003863:Depression / Q000209:etiology / Q000235:genetics*; D005060:Europe; D005260:Female; D005828:Genetics, Population; D006801:Humans; D008016:Life Change Events; D008297:Male; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013315:Stress, Psychological / Q000150:complications
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins