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Combined Effect of TLR2 Gene Polymorphism and Early Life Stress on the Age at Onset of Bipolar Disorders

  • José Oliveira,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France

  • Bruno Etain,

    Affiliations INSERM, U955, Psychiatrie Génétique, Créteil, France, Université Paris-Est, Faculté de Médecine, Créteil, France, AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France, Fondation FondaMental, Créteil, France

  • Mohamed Lajnef,

    Affiliations INSERM, U955, Psychiatrie Génétique, Créteil, France, Université Paris-Est, Faculté de Médecine, Créteil, France, Fondation FondaMental, Créteil, France

  • Nora Hamdani,

    Affiliations INSERM, U955, Psychiatrie Génétique, Créteil, France, Université Paris-Est, Faculté de Médecine, Créteil, France, AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France, Fondation FondaMental, Créteil, France

  • Meriem Bennabi,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France

  • Djaouida Bengoufa,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France

  • Aparna Sundaresh,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France

  • Arij Ben Chaabane,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France

  • Frank Bellivier,

    Affiliations INSERM, U955, Psychiatrie Génétique, Créteil, France, Université Paris-Est, Faculté de Médecine, Créteil, France, AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France, Fondation FondaMental, Créteil, France

  • Chantal Henry,

    Affiliations INSERM, U955, Psychiatrie Génétique, Créteil, France, Université Paris-Est, Faculté de Médecine, Créteil, France, AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France, Fondation FondaMental, Créteil, France

  • Jean-Pierre Kahn,

    Affiliations Service de Psychiatrie et Psychologie Clinique, CHU de Nancy, Hôpitaux de Brabois, Vandoeuvre Les Nancy, France, Fondation FondaMental, Créteil, France

  • Dominique Charron,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France, Université Paris Diderot, Sorbonne Paris-Cité, Paris, France

  • Rajagopal Krishnamoorthy,

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France

  • Marion Leboyer ,

    ‡ RT and ML are co-senior authors on this work.

    Affiliations INSERM, U955, Psychiatrie Génétique, Créteil, France, Université Paris-Est, Faculté de Médecine, Créteil, France, AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France, Fondation FondaMental, Créteil, France

  • Ryad Tamouza

    tamouza.ryad@gmail.com

    ‡ RT and ML are co-senior authors on this work.

    Affiliations INSERM, U1160, Hôpital Saint Louis, Paris, France, Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France, Fondation FondaMental, Créteil, France, Université Paris Diderot, Sorbonne Paris-Cité, Paris, France

Combined Effect of TLR2 Gene Polymorphism and Early Life Stress on the Age at Onset of Bipolar Disorders

  • José Oliveira, 
  • Bruno Etain, 
  • Mohamed Lajnef, 
  • Nora Hamdani, 
  • Meriem Bennabi, 
  • Djaouida Bengoufa, 
  • Aparna Sundaresh, 
  • Arij Ben Chaabane, 
  • Frank Bellivier, 
  • Chantal Henry
PLOS
x

Abstract

Gene-environment interactions may play an important role in modulating the impact of early-life stressful events on the clinical course of bipolar disorder (BD), particularly associated to early age at onset. Immune dysfunction is thought to be an important mechanism linking childhood trauma with early-onset BD, thus the genetic diversity of immune-related loci may account for an important part of the interindividual susceptibility to this severe subform. Here we investigated the potential interaction between genetic variants of Toll-like receptors 2 (TLR2) and 4 (TLR4), major innate immune response molecules to pathogens, and the childhood trauma questionnaire (CTQ) in age at onset of BD. We recruited 531 BD patients (type I and II or not otherwise specified), genotyped for the TLR2 rs4696480 and rs3804099 and TLR4 rs1927914 and rs11536891 single-nucleotide polymorphisms and recorded for history of childhood trauma using the CTQ. TLR2 and TLR4 risk genotype carrier state and history of childhood emotional, physical and sexual abuses were evaluated in relation to age at onset as defined by the age at first manic or depressive episode. We observed a combined effect of TLR2 rs3804099 TT genotype and reported sexual abuse on determining an earlier age at onset of BD by means of a Kaplan-Meier survival curve (p = 0.002; corrected p = 0.02). Regression analysis, however, was non-significant for the TLR2-CTQ sexual abuse interaction term. The negative effects of childhood sexual abuse on age at onset of BD may be amplified in TLR2 rs3804099 risk genotype carriers through immune-mediated pathways. Clinical characteristics of illness severity, immune phenotypes and history of early life infectious insults should be included in future studies involving large patient cohorts.

Introduction

Classically viewed as a cyclical disease, bipolar disorder (BD) is now seen as a multi-systemic, progressive chronic illness whose clinical manifestations can be underpinned by biological and environmental factors interacting in a complex manner [1,2]. This severe disorder is associated with a significant burden of psychiatric and other medical comorbidities as well as premature mortality and is the fourth cause of disease incapacity worldwide [3,4]. In addition, BD is a highly heterogeneous disorder for which identification of underlying mechanisms as well as definition of personalized therapeutic interventions is still elusive. Efforts to define homogenous subgroups have in particular enabled the identification of early-onset BD as being more familial as well as clinically and biologically more homogenous than late-onset subforms [5,6]. Admixture analyses performed in different population groups have consistently identified early-onset BD as a distinct subset associated with worse clinical outcome; severe symptoms, resistance to treatment, higher rate of suicide attempts and of comorbidities, thus suggesting that early age at onset (AAO) is a proxy for severity of BD [5,7]. In terms of mechanisms, it is noteworthy that early-life psychosocial stressors, notably emotional and sexual abuses are associated to early AAO [8,9]. Such stressful events are also known to induce acute and chronic immune/inflammatory alterations [1013] possibly leading to an increased vulnerability to diabetes, obesity, cardiovascular disorders, autoimmunity, cancer and neurodegeneration commonly observed in adults with history of childhood maltreatment [1418]. Of interest is that elevated C-reactive-protein (CRP), as well as high prevalence of cardiovascular disorders, type 2 diabetes mellitus, hypertension and obesity, are observed in early onset BD [19,20] and that some of these conditions even precede the diagnosis of BD in pediatric patients [20]. These epidemiological observations may reflect the immune/inflammatory dysfunctions possibly particularly important in early-onset BD. This could be exemplified by the pro-inflammatory gene expression signature observed in monocytes of 85% of adolescent offspring of BD patients who later developed a mood disorder as compared to the only 19% observed among adolescent healthy controls [21]. One of the proposed mechanisms is that acute stressor-mediated events may induce chronic alterations in immune/inflammatory processes in genetically predisposed individuals [12,13]. Exploring the control of innate immune responses in BD, we recently described associations between genetic variants of Toll-like receptor 2 (TLR2) and TLR4 loci and early-onset BD [22,23].

TLRs are proteins belonging to the pattern recognition receptors’ (PRR) family that initiate inflammation by sensing danger signals derived either from invading pathogens or from endogenous damaged tissue. Among eleven different TLRs identified in humans, the trans-membrane TLR2 and TLR4, the most studied ones, are the first line of immune defense against bacteria, viruses, fungi and parasites [24]. Expressed both in the periphery and in the central nervous system (CNS) as well as in the maternal-fetal interface, they are able to initiate immediate immune responses against invading pathogens with potential implications in neuropathological processes [2527]. This is of particular relevance since a variety of infectious agents viz Borna virus, Toxoplasma gondii, influenza or herpes simplex I have been associated with BD [2831]. The currently assumed mechanism, common to these infectious insults in causing such risk, is defective central/systemic immune/inflammatory responses that interfere with expression of pro-inflammatory cytokines by microglia, the resident immune cells in the CNS known to express the full repertoire of TLRs [32]. Accordingly, strong inflammatory stimulation through the TLR-mediated pathway during gestation in mice is currently regarded as a developmental paradigm of psychiatric disorders [32,33]. These models suggest an immune-mediated two-hit mechanism in which early-life infectious events interacting with a background of genetic susceptibility may install a fragile neuro-immunological homeostasis that is potentially overwhelmed by subsequent traumatic life experiences [3335].

Based on these observations, we hypothesized that the genetic potential of innate immune/inflammatory responses may variably modulate the impact of psychosocial stressors on the clinical expression of BD, assessed here by AAO used as a proxy of severity. In this cross-sectional study, we investigated potential interactions on AAO of BD between functionally-relevant TLR2/TLR4 genetic variations and reported childhood trauma, both previously showed to be independently associated with early-onset BD.

Materials and Methods

Subjects

BD patients (n = 531) meeting DSM-IV criteria [36] for BD (type I or II and NOS), admitted to three French university-affiliated psychiatric departments (Paris-Créteil, Bordeaux and Nancy), were interviewed by trained psychiatrists with the French version of the Diagnostic Interview for Genetic Studies (DIGS version 3.0) [37]. All patients were of French descent with at least three grandparents from the mainland of France and were consecutively recruited between February 2006 and January 2010. All patients were euthymic at inclusion defined by having a Montgomery-Åsberg Depression Rating Scale score [38] and a Mania Rating Scale score [39] no more than five. The AAO was defined by the age at which the first mood episode (depressive, manic or hypomanic) occurred and determined by reviewing the medical case notes and retrospective information obtained with the DIGS. The cohort was further divided in two subgroups namely early-onset and late-onset, using the AAO of 22 years as the threshold, determined on the basis of previous admixture analyses of independent sample sets [5]. Written informed consent was obtained from all participating subjects and the institutional ethical committee approved the research protocol. These patients were sampled from one large ongoing study that explored genetic and environmental risk factors of BD. Data regarding the association between TLR2/TLR4 genetic variations and BD have been previously published [22,23] and this was the same for the data regarding the association between AAO and childhood trauma [8]. To be included in this analysis, all cases had to have both a retrospective assessment of the AAO of BD, defined by the age of the first manic or depressive episode, as well as available genotypes for TLR2 or TLR4 genetic variations.

Childhood trauma assessment

History of childhood trauma was obtained using the French version of the Childhood Trauma Questionnaire (CTQ) [40] and was available for 62% of the included patients. The CTQ is a retrospective self-report instrument that examines the traumatic childhood experiences of adults and adolescents. It consists of 28-items, each one rated from 1 (never) to 5 (very often), that measure five types of childhood trauma: emotional abuse, emotional neglect, physical abuse, physical neglect and sexual abuse. A total score from 5 to 25 for each type of abuse is determined allowing the classification in four levels of maltreatment (absence, low, moderate and severe) based on cut-off scores determined for each type of trauma [41]. The CTQ has shown excellent test-retest reliability and convergent validity and the different cut-offs have been shown to have good specificity and sensitivity [41,42].

TLR2 and TLR4 genetic polymorphism studies

Four functionally-relevant TLR2 and TLR4 single-nucleotide polymorphisms (SNPs) (rs4696480, rs3804099 and rs1927914, rs11536891 respectively) were selected based on previous genetic association studies of BD [22,23]. Genomic DNA was extracted from EDTA-treated peripheral blood samples or B-lymphoblastoid cell lines using the Nucleon BACC3 kit (GE HealthCare, Chalfont St Giles, UK). The four SNPs (TLR2 intron 1 rs4696480 A/T, TLR2 exon 3 rs3804099 C/T and TLR4 promoter rs1927914 A/G and 3’UTR rs11536891 C/T) were analyzed using pre-developed TaqMan 5’-nuclease assay kits (Applied Biosystems, Foster City, CA, USA) with allele-specific fluorogenic oligonucleotide probes (C__27994607_10, C__22274563_10, C__2704048_10 and C__31784036_10, respectively), as previously reported.

Statistical analysis

Gaussian distribution of AAO was tested using the Shapiro-Wilk’s (W = 0.896, p<0.001). Non-parametric analyses were carried out, using classical Mann-Whitney U test to explore associations between TLR2 and TLR4 genetic variants and AAO as a continuous variable, for the purposes of the present study.

Association between AAO and CTQ (physical abuse, emotional abuse and sexual abuse sub-scores) was tested with the Kruskal-Wallis’ one-way analysis of variance using each CTQ sub-score as a discrete variable categorized into absent, low, moderate and severe abuse. A logistic regression analysis was performed to statistically test for the gene-environment interaction i.e. between risk genotype of TLR2 rs3804099 and the sexual abuse sub-score of the CTQ on the pattern of AAO of BD (dichotomized into early- and late-onset as described above). Finally, a Kaplan-Meier survival curve was used to analyze the combined effect of two risk variables namely TLR2 rs3804099 and CTQ sexual abuse sub-score, on AAO. The statistical power was estimated using the Freedman method for two-sample comparison of survival functions Log-rank test. The estimated power was of 80.7%, 80.5% and 82.3% respectively for the comparison of individuals having the two risk factors (TLR2 rs3804099 TT genotype and reported childhood sexual abuse) with the other groups i.e. (i) risk genotype with absence of childhood sexual abuse, (ii) non-risk genotype with reported childhood sexual abuse and (iii) absence of both risk factors. Results were corrected for multiple comparisons by means of the Bonferroni correction using a p-value of 0.005 as a marker of significance. All analyses were performed using Stata 12 and SPSS statistics 20.

Results

Both demographic and clinical characteristics of the study subjects are described in Table 1. 47.5% of BD patients (n = 252) had an early AAO (before the age of 22) while 52.5% (n = 279) a late AAO. A significant proportion of the patients that completed the CTQ report have suffered from one or other form of childhood abuse (physical, emotional or sexual) of at least low severity (61.7%). Among them, 17.9% reported physical abuse, 48.9% emotional abuse and 30.6% sexual abuse.

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Table 1. Clinical and demographic characteristics of the 531 bipolar disorder patients.

https://doi.org/10.1371/journal.pone.0119702.t001

Genotype and allele frequencies of the studied TLR2 and TLR4 genetic variants (Table 2) were in Hardy-Weinberg equilibrium and comparable to those reported in public database for Caucasians (http://www.ncbi.nlm.nih.gov).

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Table 2. Genotype frequencies of the studied TLR2 and TLR4 polymorphisms for the 531 bipolar disorder patients.

https://doi.org/10.1371/journal.pone.0119702.t002

Effects of TLR2 and TLR4 genetic polymorphism and CTQ abuse scores on age at onset of bipolar disorder

We found that the TLR2 rs3804099 TT genotype was marginally associated with an earlier AAO [p = 0.01; corrected p (pc) = 0.1] with mean AAO of 23.5±9.56 years for patients bearing the TT genotype and 25.5±9.93 years for those carrying the others (CT and CC). No association was noted for the other analyzed polymorphisms (TLR2 rs4696480, TLR4 rs1927914 and TLR4 rs11536891).

Furthermore, we found an association between severity of sexual abuse (patients classified into absent, low, moderate and severe trauma scale categories) and AAO of BD (p = 0.002; pc = 0.02). The mean AAO for patients reporting absent, low, moderate and severe sexual abuse was respectively 25.5±10.45, 25.3±8.78, 19.8±6.52 and 21.5±6.73. No such association with AAO was noted for both physical and emotional abuse.

Effect of genotype-environment interaction: effect of TLR2 rs3804099 / CTQ sexual abuse score on age at onset of BD

Schematic representation of TLR2 rs3804099 TT genotype distribution pattern and sexual abuse sub-score as a function of AAO is shown in Fig. 1. No relationship between TLR2 rs3804099 polymorphism and childhood sexual abuse on AAO of BD was observed in the logistic regression analysis. Introducing gender as a covariate in the model did not modify the observed results (data not shown) (see below in discussion section). However, using AAO of BD as a “time to event” variable in a Kaplan-Meier survival curve, we found that the presence of both TLR2 rs3804099 TT risk genotype and low to severe sexual trauma had a cumulative effect on AAO of BD (p = 0.002; pc = 0.02) (Fig. 2). For example, at the age of 20 years, 59% of those with both risk factors were already clinically affected as compared to the 37% of those without any risk factor. Co-occurrence of the TLR2 rs3804099 TT genotype (previously associated with early AAO) and reported low to severe sexual abuse had a statistically significant effect on determining early disorder-onset age when compared with any of the three other combinations.

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Fig 1. Representation of age at onset of bipolar disorder according to TLR2 genotype and reported childhood sexual abuse.

Mean ± standard deviation of bipolar disorder age at onset is represented according to Toll-like receptor 2 (TLR2) rs3804099 risk genotype carrier state and reported sexual abuse as defined by the Childhood Trauma Questionnaire (CTQSSA).

https://doi.org/10.1371/journal.pone.0119702.g001

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Fig 2. Kaplan-Meier survival curve of age at onset of bipolar disorder.

Patients were stratified in four groups according to TLR2 (Toll-like receptor 2) rs3804099 TT risk genotype carrier state and reported childhood sexual abuse as defined by the Childhood Trauma Questionnaire (CTQSSA) and age at onset defined as a time-to-event variable in a Kaplan-Meier survival curve (p = 0.002; corrected p = 0.02).

https://doi.org/10.1371/journal.pone.0119702.g002

Discussion

It is well established that childhood traumatic experiences are associated with increased severity of BD, namely with an earlier age at onset (AAO), but possible interaction between environmental factors such as stress and genetic background is unknown [8]. Knowing that stress is a major inducer of inflammatory responses [11], we explored here the interaction between immunogenetic variations and presence of early and severe stress in a sample of BD patients. We observed a combined effect of both a genetic variant of TLR2, a major trigger of peripheral and central inflammatory responses, and reported childhood sexual abuse on the AAO, a proxy of increased severity of psychiatric and somatic manifestations in BD [7]. Thus, we propose that TLR2 rs3804099 TT genotype carriers may be more susceptible to inflammation-mediated damage induced by early stress with consequent earlier AAO of BD.

Early-life trauma is associated with permanent alterations of the immune system, namely development of chronic mild inflammation (CRP) [13] and stronger inflammatory responses (IL-6) subsequently to stress exposures [10]. Inflammation has also been suggested to be involved in the mechanisms underlying the comorbidity between metabolic syndrome and psychiatric disorders and causing premature mortality in individuals with a history of childhood adversity [11,43,44]. Childhood inflammation (IL-6) has been recently demonstrated to even precede the diagnosis of depression and psychosis in a prospectively followed general population cohort [45]. The genetic diversity of immune-related genes could thus be implicated in the inter-individual vulnerability to such stressors.

So far, genes linked to biological stress response systems viz. the hypothalamic-pituitary-adrenal axis (FKBP5), the monoaminergic system (SLC6A4, COMT) and the neurotrophic support of the CNS (BDNF), provided logical candidate genes to test for gene-environment interactions in several studies and confirmed the suspected genetic vulnerability and epigenetic changes to stressful/traumatic life events in psychiatric settings [4653]. However, these molecules are not in direct relationship with the potential environmental risk factors as it is the case with TLR2, a sensor of BD-associated neurotropic pathogens [5456]. This is of importance as prenatal immune priming through the TLR-mediated pathway and peripubertal stress exposure synergistically induced behavioral changes, unbalanced neurotransmitter levels and enhanced the expression of markers of inflammation and of microglia activation in stress sensitive brain areas of mice [35]. TLR2 molecules are pivotal both in homeostasis and in immune surveillance of the CNS [57]. Indeed, neuroinflammation can be elicited through the TLR2-mediated pathway either by endogenous molecules such as α-synuclein and amyloid β-peptide in Parkinson and Alzheimer disorders respectively [58,59] or by infectious insult as previously demonstrated for herpes simplex virus type 1 [60]. Moreover, associations between the TLR2 genetic diversity and Alzheimer’s disease [61] or cognitive function in schizophrenia [62] are highly suggestive of genetically-driven inter-individual ability to modulate neuroinflammatory processes. Of importance is that the TLR2 rs3804099 polymorphism was showed on the one hand to be associated with several inflammatory and infectious diseases including pulmonary tuberculosis, neonatal infection, filariasis, ocular Behcet’s disease and cancer [6367] and to exert a functional impact on the inflammatory response on the other [65,68,69].

It is plausible to hypothesize that TLR2 rs3804099 TT genotype carriers may be more susceptible to certain infectious insults and/or more prone to inflammation-mediated damage in presence of stress. TLR2, but not TLR4, has also been implicated in the perpetuation of inflammatory responses in the CNS after pro-inflammatory stimulation of astrocytes [70] and involved in hippocampal neurogenesis as mice lacking TLR2 displayed impaired hippocampal and neuronal differentiation, which was not observed for TLR4 [71]. These observations could be related to the TLR2 specificity of our findings especially as hippocampal alterations have been repeatedly reported in adults with a history of childhood traumatic experiences and are suggested to be involved in the pathophysiology of BD [7274].

Our regression analysis yielded a non-significant TLR2-CTQ interaction term, likely indicating that our results, while suggestive, are not robustly indicative of gene-environment interaction. Many genes with small effects are involved in the etiology of BD interacting with numerous environmental stressors. This may be one of the reasons for not detecting significance in regression analysis, leaving aside the limited sample size. However, a combined effect is observed in determining an earlier AAO in our patients when performing a Kaplan-Meyer survival curve. Since gender is a critical issue in BD as well as in the susceptibility to trauma, futures studies involving much more larger patient cohorts are warranted to address the issue. Indeed, we failed to observe any difference after sex-based stratification, possibly due to the sample size.

TLR2 genetic susceptibility probably contributes to the neuro-immunological responses to pre- and perinatal infections establishing a lower threshold for subsequent stress-triggered pathological responses leading to a more severe clinical presentation. Such severity should be investigated in future studies including outcomes such as global functioning, cognition, suicidality, number and duration of mood episodes and development of comorbid conditions such as metabolic syndrome or autoimmune thyroiditis. Given the present findings, it would also be of interest to investigate the susceptibility conferred by this TLR2 polymorphism to BD-associated pathogens like Toxoplasma gondii and the relationship between perinatal infections and childhood traumatic events on immune and clinical phenotypes of BD. Associations with infectious stigma, as well as markers of inflammation and stress components (e.g. cortisol) could not be explored as they were not available in our cohort. We deliberately chose to study euthymic patients to minimize the potential recall bias of traumatic childhood experiences associated with mood state. Moreover, the patients included in this study are from the mainland of France and of French descent with equal access to medical care (French social security system). Thus we cannot extrapolate these observations to BD in other populations socio-culturally and genetically distinct.

We propose that both risk factors, genetic polymorphism of TLR2 and sexual abuse, independently found in earlier studies to be associated with earlier AAO, act cumulatively in immune-related pathways contributing to increase the “allostatic load” in BD. Further studies are warranted to sustain this model which may open the way to novel therapeutic targets and to personalized medicine based on one’s genetic background and history of exposure to environmental risk factors.

Acknowledgments

We thank patients with bipolar disorder and controls who agreed to participate in this study. We thank the Cochin Hospital cell repository, the Clinical Centre of Investigations, the Biological Resources Centre) of Mondor Hospital, and the blood bank Centre of EFS Créteil (for technical assistance. We thank the FondaMental Foundation.

J. Oliveira acknowledges the financial support of the Foundation for Science and Technology (Portugal) doctoral degree grant (SFRH/BD/76170/2011).

Author Contributions

Conceived and designed the experiments: JO BE M. Lajnef DC RK M. Leboyer RT. Performed the experiments: JO MB DB AS AB. Analyzed the data: JO BE M. Lajnef RT. Contributed reagents/materials/analysis tools: BE NH FB CH JPK. Wrote the paper: JO BE M. Leboyer RK RT.

References

  1. 1. Leboyer M, Kupfer DJ. Bipolar disorder: new perspectives in health care and prevention. J Clin Psychiatry. 2010;71: 1689–1695. pmid:21190640
  2. 2. Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373: 234–239. pmid:19150704
  3. 3. Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, et al. Grand challenges in global mental health. Nature. 2011;475: 27–30. pmid:21734685
  4. 4. Gore FM, Bloem PJ, Patton GC, Ferguson J, Joseph V, Coffey C, et al. Global burden of disease in young people aged 10–24 years: a systematic analysis. Lancet. 2011;377: 2093–2102. pmid:21652063
  5. 5. Geoffroy PA, Etain B, Scott J, Henry C, Jamain S, Leboyer M, et al. Reconsideration of bipolar disorder as a developmental disorder: Importance of the time of onset. J Physiol Paris. 2013;107: 278–285. pmid:23542544
  6. 6. Leboyer M, Henry C, Paillere-Martinot ML, Bellivier F. Age at onset in bipolar affective disorders: a review. Bipolar Disord. 2005;7: 111–118. pmid:15762851
  7. 7. Etain B, Lajnef M, Bellivier F, Mathieu F, Raust A, Cochet B, et al. Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States. J Clin Psychiatry. 2012;73: e561–566. pmid:22579163
  8. 8. Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74: 991–998. pmid:24229750
  9. 9. Etain B, Henry C, Bellivier F, Mathieu F, Leboyer M. Beyond genetics: childhood affective trauma in bipolar disorder. Bipolar Disord. 2008;10: 867–876. pmid:19594502
  10. 10. Carpenter LL, Gawuga CE, Tyrka AR, Lee JK, Anderson GM, Price LH. Association between plasma IL-6 response to acute stress and early-life adversity in healthy adults. Neuropsychopharmacol. 2010;35: 2617–2623.
  11. 11. Coelho R, Viola TW, Walss-Bass C, Brietzke E, Grassi-Oliveira R. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand. 2014;129: 180–192. pmid:24205846
  12. 12. Copeland WE, Wolke D, Lereya ST, Shanahan L, Worthman C, Costello EJ. Childhood bullying involvement predicts low-grade systemic inflammation into adulthood. Proc Natl Acad Sci U S A. 2014;111: 7570–7575. pmid:24821813
  13. 13. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104: 1319–1324. pmid:17229839
  14. 14. Kelly-Irving M, Lepage B, Dedieu D, Lacey R, Cable N, Bartley M, et al. Childhood adversity as a risk for cancer: findings from the 1958 British birth cohort study. BMC Public Health. 2013;13: 767. pmid:23957659
  15. 15. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull. 2011;137: 959–997. pmid:21787044
  16. 16. Rich-Edwards JW, Spiegelman D, Lividoti Hibert EN, Jun HJ, Todd TJ, Kawachi I, et al. Abuse in childhood and adolescence as a predictor of type 2 diabetes in adult women. Am J Prev Med. 2010;39: 529–536. pmid:21084073
  17. 17. Shonkoff JP, Garner AS, Committee on Psychosocial Aspects of Child and Family Health, Committee on Early Childhood, Adoption, and Dependent Care, Section on Developmental and Behavioral Pediatrics. The lifelong effects of early childhood adversity and toxic stress. Pediatrics. 2012;129: e232–246. pmid:22201156
  18. 18. Slopen N, Koenen KC, Kubzansky LD. Childhood adversity and immune and inflammatory biomarkers associated with cardiovascular risk in youth: a systematic review. Brain Behav Immun. 2012;26: 239–250. pmid:22138616
  19. 19. Goldstein BI, Collinger KA, Lotrich F, Marsland AL, Gill MK, Axelson DA, et al. Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders. J Child Adolesc Psychopharmacol. 2011;21: 479–484. pmid:22040193
  20. 20. Jerrell JM, McIntyre RS, Tripathi A. A cohort study of the prevalence and impact of comorbid medical conditions in pediatric bipolar disorder. J Clin Psychiatry. 2010;71: 1518–1525. pmid:20584522
  21. 21. Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJT, et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry. 2008;65: 395–407. pmid:18391128
  22. 22. Oliveira J, Busson M, Etain B, Jamain S, Hamdani N, Boukouaci W, et al. Polymorphism of Toll-like receptor 4 gene in bipolar disorder. J Affect Disord. 2014;152–154: 395–402. pmid:25618002
  23. 23. Oliveira J, Hamdani N, Busson M, Etain B, Bennabi M, Amokrane K, et al. Association between toll-like receptor 2 gene diversity and early-onset bipolar disorder. J Affect Disord. 2014;165: 135–141. pmid:24882191
  24. 24. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124: 783–801. pmid:16497588
  25. 25. Hanke ML, Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond). 1979. 2011;121: 367–387. pmid:21745188
  26. 26. Koga K, Izumi G, Mor G, Fujii T, Osuga Y. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications. Am J Reprod Immuno. 1989. 2014;72: 192–205.
  27. 27. Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173: 3916–3924. pmid:15356140
  28. 28. Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Cole S, Krivogorsky B, et al. Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biol Psychiatry. 2004;55: 588–593. pmid:15013827
  29. 29. Fu ZF, Amsterdam JD, Kao M, Shankar V, Koprowski H, Dietzschold B. Detection of Borna disease virus-reactive antibodies from patients with affective disorders by western immunoblot technique. J Affect Disord. 1993;27: 61–68. pmid:8432962
  30. 30. Hamdani N, Daban-Huard C, Lajnef M, Richard JR, Delavest M, Godin O, et al. Relationship between Toxoplasma gondii infection and bipolar disorder in a French sample. J Affect Disord. 2013;148: 444–448. pmid:23273549
  31. 31. Parboosing R, Bao Y, Shen L, Schaefer CA, Brown AS. Gestational influenza and bipolar disorder in adult offspring. JAMA Psychiatry. 2013;70: 677–685. pmid:23699867
  32. 32. Meyer U. Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry. 2014;75: 307–315. pmid:23938317
  33. 33. Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75: 324–331. pmid:24286760
  34. 34. Bayer TA, Falkai P, Maier W. Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the “two hit hypothesis.” J Psychiatr Res. 1999;33: 543–548. pmid:10628531
  35. 35. Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R, et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science. 2013;339: 1095–1099. pmid:23449593
  36. 36. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Paris: Masson; 1994.
  37. 37. Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry. 1994;51: 849–859; discussion 863–864. pmid:7944874
  38. 38. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry J Ment Sci. 1979;134: 382–389.
  39. 39. Bech P, Rafaelsen OJ, Kramp P, Bolwig TG. The mania rating scale: scale construction and inter-observer agreement. Neuropharmacology. 1978;17: 430–431. pmid:673161
  40. 40. Paquette D, Laporte L, Bigras M, Zoccolillo M. [Validation of the French version of the CTQ and prevalence of the history of maltreatment]. Sante Ment Que. 2004;29: 201–220. pmid:15928793
  41. 41. Bernstein DP, Fink L. Childhood Trauma Questionnaire: A Retrospective Self-report: Manual. Harcourt Brace & Company; 1998.
  42. 42. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151: 1132–1136. pmid:8037246
  43. 43. Kelly-Irving M, Lepage B, Dedieu D, Bartley M, Blane D, Grosclaude P, et al. Adverse childhood experiences and premature all-cause mortality. Eur J Epidemiol. 2013;28: 721–734. pmid:23887883
  44. 44. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21: 901–912. pmid:17475444
  45. 45. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of Serum Interleukin 6 and C-Reactive Protein in Childhood With Depression and Psychosis in Young Adult Life: A Population-Based Longitudinal Study. JAMA Psychiatry. 2014;71: 1121–1128. pmid:25133871
  46. 46. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299: 1291–1305. pmid:18349090
  47. 47. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301: 386–389. pmid:12869766
  48. 48. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16: 33–41. pmid:23201972
  49. 49. Miller S, Hallmayer J, Wang PW, Hill SJ, Johnson SL, Ketter TA. Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course. J Psychiatr Res. 2013;47: 252–258. pmid:23182421
  50. 50. Perroud N, Jaussent I, Guillaume S, Bellivier F, Baud P, Jollant F, et al. COMT but not serotonin-related genes modulates the influence of childhood abuse on anger traits. Genes Brain Behav. 2010;9: 193–202. pmid:20002200
  51. 51. Perroud N, Courtet P, Vincze I, Jaussent I, Jollant F, Bellivier F, et al. Interaction between BDNF Val66Met and childhood trauma on adult’s violent suicide attempt. Genes Brain Behav. 2008;7: 314–322. pmid:17883407
  52. 52. Romens SE, McDonald J, Svaren J, Pollak SD. Associations Between Early Life Stress and Gene Methylation in Children. Child Dev. 2014; [Epub ahead of print].
  53. 53. Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65: 760–769. pmid:19150054
  54. 54. Cai M, Li M, Wang K, Wang S, Lu Q, Yan J, et al. The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-κB through the Toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway. PloS One. 2013;8: e54586. pmid:23382920
  55. 55. Debierre-Grockiego F, Campos MA, Azzouz N, Schmidt J, Bieker U, Resende MG, et al. Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from Toxoplasma gondii. J Immunol. 2007;179: 1129–1137. pmid:17617606
  56. 56. Mun HS, Aosai F, Norose K, Chen M, Piao LX, Takeuchi O, et al. TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection. Int Immunol. 2003;15: 1081–1087. pmid:12917260
  57. 57. Rivest S. Regulation of innate immune responses in the brain. Nat Rev Immunol. 2009;9: 429–439. pmid:19461673
  58. 58. Kim C, Ho DH, Suk JE, You S, Michael S, Kang J, et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013;4: 1562. pmid:23463005
  59. 59. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, et al. TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. J Immunol. 2012;188: 1098–1107. pmid:22198949
  60. 60. Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J Immunol. 2005;175: 4189–4193. pmid:16177057
  61. 61. Yu JT, Mou SM, Wang LZ, Mao CX, Tan L. Toll-like receptor 2–196 to-174 del polymorphism influences the susceptibility of Han Chinese people to Alzheimer’s disease. J Neuroinflammation. 2011;8: 136. pmid:21989233
  62. 62. Kang WS, Park JK, Lee SM, Kim SK, Park HJ, Kim JW. Association between genetic polymorphisms of Toll-like receptor 2 (TLR2) and schizophrenia in the Korean population. Gene. 2013;526: 182–186. pmid:23644137
  63. 63. Abu-Maziad A, Schaa K, Bell EF, Dagle JM, Cooper M, Marazita ML, et al. Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res. 2010;68: 323–329. pmid:20463618
  64. 64. Arji N, Busson M, Iraqi G, Bourkadi JE, Benjouad A, Bouayad A, et al. Genetic diversity of TLR2, TLR4, and VDR loci and pulmonary tuberculosis in Moroccan patients. J Infect Dev Ctries. 2014;8: 430–440. pmid:24727508
  65. 65. Fang J, Hu R, Hou S, Ye Z, Xiang Q, Qi J, et al. Association of TLR2 gene polymorphisms with ocular Behcet’s disease in a Chinese Han population. Invest Ophthalmol Vis Sci. 2013;54: 8384–8392. pmid:24255044
  66. 66. Junpee A, Tencomnao T, Sanprasert V, Nuchprayoon S. Association between Toll-like receptor 2 (TLR2) polymorphisms and asymptomatic bancroftian filariasis. Parasitol Res. 2010;107: 807–816. pmid:20549240
  67. 67. Wang X, Li J, Xie W, Zhang W, Chang Y. Toll-like receptor 2 gene polymorphisms and cancer susceptibility: a meta-analysis. Neoplasma. 2013;60: 459–467. pmid:23581420
  68. 68. Chen KH, Gu W, Zeng L, Jiang DP, Zhang LY, Zhou J, et al. Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock. 2011;35: 35–41. pmid:20577149
  69. 69. Zhang F, Gao XD, Wu WW, Gao Y, Zhang YW, Wang SP. Polymorphisms in toll-like receptors 2, 4 and 5 are associated with Legionella pneumophila infection. Infection. 2013;41: 941–948. pmid:23526294
  70. 70. Henn A, Kirner S, Leist M. TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes. J Immunol. 2011;186: 3237–3247. pmid:21282508
  71. 71. Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, et al. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol. 2007;9: 1081–1088. pmid:17704767
  72. 72. Femenía T, Gómez-Galán M, Lindskog M, Magara S. Dysfunctional hippocampal activity affects emotion and cognition in mood disorders. Brain Res. 2012;1476: 58–70. pmid:22541166
  73. 73. Frey BN, Andreazza AC, Nery FG, Martins MR, Quevedo J, Soares JC, et al. The role of hippocampus in the pathophysiology of bipolar disorder. Behav Pharmacol. 2007;18: 419–430. pmid:17762510
  74. 74. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997;27: 951–959. pmid:9234472