Peter Petschner1,2, Xenia Gonda1,2,3, Gabor Hullam2,4, Peter Antal2,4, Nora Eszlari1,2,8, Tomas GM Hökfelt5, Ian M Anderson6, John Francis William Deakin6, Gabriella Juhasz1,2,6,7, Gyorgy Bagdy1,2,8
1Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; 2MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; 3Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary, 4Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary; 5Retzius Laboratory, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; 6Neuroscience and Psychiatry Unit, The University of Manchester, Manchester, United Kingdom and Manchester Academic Health Sciences Centre, Manchester, United Kingdom; 7SE-NAP2 Genetic Brain Imaging Migraine Research Group, Semmelweis University, Budapest, Hungary; 8NAP2-SE New Antidepressant Target Research Group, Semmelweis University, Budapest, Hungary
Depression and anxiety-related phenotypes are significantly influenced by environmental stress exposures, suggesting that effects of genetic factors are altered by specific environmental conditions. The polymorphism of the serotonin transporter, 5-HTTLPR, was demonstrated to interact with environmental stress on depression susceptibility, but an effect was refuted by a recent meta-analysis.
The aim of the present work was to test whether there are more relevant polymorphisms behind depression and related phenotypes than 5-HTTLPR.
We investigated 6 candidate polymorphisms (rs6265 in BDNF, rs8836 in GALR2, rs7766029 in CB1, rs6311 in HTR2A, rs7958311 in P2RX7, rs6295 in HTR1A) in addition to 5-HTTLPR on an aggregate depression/anxiety-phenotype in a complex model with Bayesian network based Bayesian multi-level analysis of relevance. The 1682 individuals were categorized into low, moderate and high-exposed groups based on recent negative life event exposure (low=0-1, moderate=2, high=3/more) and analyses run separately.
No relevant [posterior probability (pr)>0.5] genetic factors were found in the low-exposed group. SNPs rs6265 (BDNF) and rs8836 (GALR2) were relevant with pr=0.74 and pr=0.84, respectively, in the moderate-exposure group and rs7958311 (P2RX7), rs6295 (HTR1A) and rs6265 (BDNF) (pr=0.62, pr=0.59, pr=0.57, respectively) in the high exposure group. Interestingly, while effects of 5-HTTLPR seemed to increase with stress exposure on our aggregate phenotype, it could not reach the relevance threshold of 0.5.
These results suggest that the pharmacologically grounded 5-HTTLPR is a less important factor and future research should focus on the BDNF, GALR2, P2RX7, HTR1A genes as potential targets for therapies behind depression and anxiety in stress exposed patient groups.
The study was supported by NEWMOOD (LSHM-CT-2004-503474); TAMOP-4.2.1.B-09/1/KMR-2010-0001; KTIA_13_NAP-A-II/14, KTIA_NAP_13-1-2013-0001; KTIA_NAP_13-2-2015-0001; 2017-1.2.1- NKP-2017- 00002; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group; OTKA 119866. Peter Petschner was supported by the ÚNKP-17-4-I-SE-8 New National Excellence Program of the Ministry of Human Capacities.
New National Excellence Program of the Ministry of Human Capacities
Supervisor: Gyorgy Bagdy