Elsevier

Brain, Behavior, and Immunity

Volume 67, January 2018, Pages 203-210
Brain, Behavior, and Immunity

Full-length Article
Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples

https://doi.org/10.1016/j.bbi.2017.08.023Get rights and content

Highlights

  • Gene-environment study focusing on comprehensive analysis of immune candidate genes.

  • Interaction with childhood maltreatment in predicting recurrent depression.

  • Loci identified in the discovery sample taken forward to an independent replication sample.

  • Two loci present some evidence for replication in IL-6 and CRP.

  • These loci should be targeted for replication in further studies internationally in the future.

Abstract

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD = 0.059, SE = 0.016, p < 0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q = 0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD = 0.092, SE = 0.029, p = 0.002), but less compelling evidence in the replication sample alone (recurrent MDD q = 0.198; all MDD q = 0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.

Introduction

Major depressive disorder (MDD) is a highly prevalent disorder that represents a substantial economic as well as clinical burden (Mortality and Causes of Death, 2016). Heritability has been well-established and estimates from population-based studies range between 31 and 42% (Sullivan et al., 2000), with higher estimates of around 70% based on clinical or more severe cases (McGuffin et al., 2007). Many studies have attempted to identify genes associated with the disorder, however despite significant improvements in genotyping platforms, and large-scale increases in sample sizes, consistently replicated genetic variants remain elusive (Major Depressive Disorder Working Group of the Psychiatric Consortium et al., 2013). This may be for multiple reasons, including failure of most association studies to take into account the role of stress in the development of MDD (Cohen-Woods et al., 2013, Hosang et al., 2012, Thapar et al., 2012).

The first reported specific gene–environment (GE) interaction in MDD was with the serotonin transporter polymorphism, 5HTTLPR and this has proven controversial (Uher and McGuffin, 2010). Recent meta-analyses indicate that the variable being measured (i.e. childhood stress vs. adult recent stress vs. medical illness) can impact findings, and highlight the need for replication (Karg et al., 2011), with the most recent failing to confirm a robust GE interaction with the 5HTTLPR and life events (Culverhouse et al., 2017). GE studies face significant methodological challenges with recommendations for future candidate gene-environment studies including: reporting all statistical tests conducted for a novel candidate GE study, applying appropriate corrections for statistical testing, and replication (Duncan et al., 2014).

Elevated inflammation has been associated with both MDD and exposure to childhood traumatic events. Our study focuses on genes where proteins in the periphery have been associated with both MDD and childhood maltreatment (CRP, IL-6, TNF), genes where GE interactions have previously been reported that include childhood or adolescent stressors (IL-1b, IL6), or genes associated with anti-depressant response in caucasian MDD patients (IL-11); poor anti-depressant response has been reported in individuals with a history of childhood maltreatment (Williams et al., 2016). Elevations of many inflammatory proteins have been reported in patients with MDD including C-reactive protein (CRP), tumour necrosis factor (TNF), and interleukin-6 (IL-6) (Dowlati et al., 2010, Howren et al., 2009). Further, psychological stressors, including early-life maltreatment, have been consistently associated with elevated inflammatory markers (Baumeister et al., 2016, Danese et al., 2008, Fagundes et al., 2013, Kiecolt-Glaser et al., 2011), supported by animal models (Ganguly and Brenhouse, 2015).

Most studies to date have focused on protein analyses, and are limited in number; many more studies have genetic data available rather than serum or plasma, which is necessary for peripheral protein analyses. For this reason investigating genetic variants that have potential to impact gene- and protein-expression in the context of stressful life events is of value. There is also some evidence for interaction with genetic variants in IL-1b and IL-6 and chronic recent stress exposure predicting depressive scores in Australian youth (Tartter et al., 2015), and IL-1b predicting depressive symptoms in preschoolers exposed to childhood maltreatment (Ridout et al., 2014), and IL-11 with anti-depressant response (Uher et al., 2010). Other genes in the inflammation pathway have been associated with anti-depressant response (e.g. (Barnes et al., 2017, Wong et al., 2008), however as our populations are caucasian, for this study we restricted to genes identified in Caucasian populations. Thus overall there are sound reasons for exploring genes involved in inflammation in GE research, looking at depressive disorder onset, course and exposure to stressors including childhood maltreatment (Baumeister et al., 2016, Grosse et al., 2016, Kiecolt-Glaser et al., 2015, Miller and Raison, 2016).

In this paper we present the first investigation of the interaction between exposure to childhood stress and genetic variation, as captured by array, within the inflammation pathway. We focus on genes based on proteins and/or genes previously implicated in depression and with childhood maltreatment directly (CRP, IL1b, IL-6, IL11, and TNF), and indirectly (TNFR1, and TNFR2) (Camara et al., 2015, Danese et al., 2008, Goldsmith et al., 2016, Kiecolt-Glaser et al., 2015). This study aimed to address the recommendations by Duncan et al. (Duncan et al., 2014): including previously implicated GE loci (IL-6 (rs1800795) and IL-1b (rs16944)) (Tartter et al., 2015), by clearly reporting all statistical tests run, robust multiple testing correction and reporting, and independent replication, extended to a meta-analysis.

Section snippets

Discovery sample

Individuals were drawn from the Radiant MDD cohort recruited in the United Kingdom from three sites (Birmingham, Cardiff, and London), described in detail previously (Fisher et al., 2013, Lewis et al., 2010). In brief, MDD cases experienced a minimum of two DSM-IV/ICD-10 depressive episodes of moderate to severe severity (First, 1994), ascertained by interview in person with the Schedules Clinical Assessments Neuropsychiatry (SCAN) (Wing et al., 1990); DNA was extracted from whole blood.

RADIANT discovery sample

All forms of childhood maltreatment were significantly associated with greater risk of recurrent depression (Supplementary Table 1 for association, and Supplementary Table 10 for frequencies). All genotypes were in Hardy Weinberg Equilibrium, and there were no significant main effects of genotype on recurrent depression in the discovery Radiant sample, including adjustment for gender (Supplementary Table 2). No significant differences in overall severity of maltreatment was found by genotype

Discussion

We found evidence for interaction between childhood adversity and one SNP in IL-6 (rs1818879) in the RADIANT sample; the Münster replication sample also presented evidence prior to correction, which reduced to very close to significance following correction for multiple testing. It is notable that for replication, we maintained two-tail significance tests; had a one-tail test been applied this would have reached significance even following correction. Due to the controversies that have arisen

Conclusion

Here we present suggestive evidence for novel interaction loci in IL-6 (rs1818879) and potentially CRP (rs3093077) in the context of childhood maltreatment, increasing risk of recurrent depression (IL-6) and non-recurrent depression (CRP). Although we have described and discussed the results for both these SNPs, we must highlight that independent replication analyses fell short of significance, although relatively marginal in terms of rs1818879. To address restricted power we also ran

Acknowledgments

We thank all the participants of the studies for their generous contribution. Funding: This paper represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. SC-W was supported by an NIHR Biomedical Research Centre

Conflicts

AF and PM have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies including GlaxoSmithKline. BB have received honoraria for speaking and participating in expert panels for pharmaceutical companies including Lundbeck, Pfizer, and AstraZeneca. VA declares that over the last three years he has received compensations for his contributions as member of advisory boards and for presentations for the following companies: Astra-Zeneca, Eli Lilly,

Author contributions

SCW designed the study, genetic analysis, statistical analysis, sample and genotyping of RADIANT and Münster sample, writing of manuscript; DA statistical analysis, and manuscript review; KD bioinformatic data extraction, and manuscript review; HLF childhood maltreatment data management, contributed to data interpretation and manuscript review; DS taqman genotyping, contributed to data interpretation and manuscript review; GMH contributed to data interpretation and manuscript review; AK, MO, NC

References (54)

  • A. Thapar et al.

    Depression in adolescence

    Lancet

    (2012)
  • P.P. Amaral et al.

    Non-coding RNAs in homeostasis, disease and stress responses: an evolutionary perspective

    Brief. Funct. Genomics

    (2013)
  • J. Barnes et al.

    Genetic contributions of inflammation to depression

    Neuropsychopharmacology

    (2017)
  • D. Baumeister et al.

    Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α

    Mol. Psychiatry

    (2016)
  • Y. Benjamini et al.

    Controlling the false discovery rate: a practical and powerful approach to multiple testing

    J. R. Stat. Soc. Ser. B (Methodological)

    (1995)
  • J. Bick et al.

    Childhood adversity and DNA methylation of genes involved in the hypothalamus-pituitary-adrenal axis and immune system: whole-genome and candidate-gene associations

    Dev. Psychopathol.

    (2012)
  • S. Cohen-Woods et al.

    The current state of play on the molecular genetics of depression

    Psychol. Med.

    (2013)
  • R.C. Culverhouse et al.

    Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

    Mol. Psychiatry

    (2017)
  • A. Danese et al.

    Elevated inflammation levels in depressed adults with a history of childhood maltreatment

    Arch. General Psychiatry

    (2008)
  • D.M. Dick

    Gene-environment interaction in psychological traits and disorders

    Annu. Rev. Clin. Psychol.

    (2011)
  • L.E. Duncan et al.

    Mind the gap: Why many geneticists and psychological scientists have discrepant views about gene–environment interaction (G×E) research

    Am. Psychol.

    (2014)
  • First, M.B., 1994. Diagnostic and Statistical Manual of Mental Disorders. DSM IV-4th edition....
  • R.A. García-Ramírez et al.

    TNF, IL6, and IL1B polymorphisms are associated with severe influenza A (H1N1) virus infection in the mexican population

    PLoS One

    (2015)
  • D. Goldsmith et al.

    A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression

    Mol. Psychiatry

    (2016)
  • Hosang, G.M., Korszun, A., Jones, L., Jones, I., McGuffin, P., Farmer, A.E., 2012. Life-event specificity: bipolar...
  • B.N. Howie et al.

    A flexible and accurate genotype imputation method for the next generation of genome-wide association studies

    PLoS Genet.

    (2009)
  • M.B. Howren et al.

    Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis

    Psychosom. Med.

    (2009)
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