P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms

Zsuliet Kristof; Nora Eszlari; Sara Sutori; Zsofia Gal; Dora Torok; Daniel Baksa; Peter Petschner; Beata Sperlagh; Ian M Anderson; John Francis William Deakin; Gabriella Juhasz; Gyorgy Bagdy; Xenia Gonda

doi:10.1371/journal.pone.0252766

P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms

PLoS One. 2021 Jun 10;16(6):e0252766. doi: 10.1371/journal.pone.0252766. eCollection 2021.

Authors

Zsuliet Kristof^{1

2

3}, Nora Eszlari^{4

5}, Sara Sutori^{4

6}, Zsofia Gal⁴, Dora Torok⁴, Daniel Baksa^{4

7}, Peter Petschner^{4

8}, Beata Sperlagh², Ian M Anderson⁹, John Francis William Deakin⁹, Gabriella Juhasz^{4

7

8}, Gyorgy Bagdy^{4

5

8}, Xenia Gonda^{3

5

8}

Affiliations

¹ Doctoral School of Mental Health Sciences, Semmelweis University, Budapest, Hungary.
² Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Budapest, Hungary.
³ Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
⁴ Faculty of Pharmacy, Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
⁵ NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary.
⁶ Faculty of Humanities and Social Sciences, Institute of Psychology, Pazmany Peter Catholic University, Budapest, Hungary.
⁷ SE-NAP-2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary.
⁸ MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
⁹ Faculty of Biological, Division of Neuroscience and Experimental Psychology, Neuroscience and Psychiatry Unit, School of Biological Sciences, Medical and Human Sciences, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.

Abstract

The P2X purinoceptor 7 (P2RX7) mediates inflammatory microglial responses and is implicated in neuroimmune mechanisms of depression and neurodegenerative disorders. A number of studies suggest that psychosocial stress may precipitate depression through immune activation. Genetic association studies of P2RX7 variants with depression have been inconclusive. However, nearly all studies have focused on only one single-nucleotide polymorphism (SNP) and have not considered interaction with psychosocial stress. We investigated the effect of several variations in P2RX7 gene using a clumping method in interaction with early adversities and recent stress on depression severity. 1752 subjects provided information on childhood adversities, recent life events, and current depression severity. Participants were genotyped for 681 SNPs in the P2RX7 gene, 335 of them passed quality control and were entered into linear regression models followed by a clumping procedure for main effect and interactions. No significant main effect was observed. Rs74892325 emerged as a top SNP for interaction with childhood adversities and rs61953400 for interaction with recent life events. Our study is the first to investigate several variants in the P2RX7 gene and in interaction with two types of stress, extending our understanding of neuroinflammation in depression, and supporting that the majority of genes influence depression by enhancing sensitivity to stressors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Adverse Childhood Experiences / psychology*
Child
Computer Simulation
Depression / genetics*
Depression / psychology*
Female
Genetic Predisposition to Disease*
Genetic Variation*
Genome, Human
Humans
Linear Models
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics
Receptors, Purinergic P2X7 / genetics*
Severity of Illness Index*
Stress, Psychological / genetics*
Young Adult

Substances

P2RX7 protein, human
Receptors, Purinergic P2X7

Associated data

figshare/10.6084/m9.figshare.13483011

Grants and funding

The study group (not individual authors) was supported by the Sixth Framework Programme of the European Union (NewMood, LSHM-CT-2004-503474); by the Hungarian Brain Research Program (Grants KTIA_13_NAPA-II/14 and 2017-1.2.1-NKP-2017-00002), and the National Development Agency (Grant KTIA_NAP_13-1-2013-0001); by the Hungarian Academy of Sciences, Hungarian National Development Agency, Semmelweis University and the Hungarian Brain Research Program (Grant KTIA_NAP_13-2-2015-0001, MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group); by the Hungarian Academy of Sciences (MTA-SE Neuropsychopharmacology and Neurochemistry Research Group); by OTKA 119866 and 131629; by TAMOP-4.2.1.B-09/1/KMR-2010-0001; by the National Research, Development and Innovation Office, Hungary (2019-2.1.7-ERA-NET-2020-00005), under the frame of ERA PerMed (ERA-PERMED2019-108); and by the Thematic Excellence Programme (Tématerületi Kiválósági Program, 2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Neurology and Translational Biotechnology thematic programmes of the Semmelweis University and the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska Curie grant agreement No. 766124. Ms. Sara Sutori was supported by ÚNKP-19-1-I-PPK, Dr. Nora Eszlari by ÚNKP-20-4-II-SE-9 and Mr. Daniel Baksa by ÚNKP-20-3-II-SE-51, by the New National Excellence Program of The Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.