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Additional file 2. Table S2: Pairwise comparison of the epigenomic data according to the staining and sorting results.

Additional file 3. Table S3: Pairwise comparison of the epigenomic data between donors and patients, ranked according to the staining and sorting results.

Additional file 1. Table S1: Comparison of the cumulated epigenomic data of the washed spermatozoa of semen donors with the cumulated epigenomic data of the washed spermatozoa of infertile patients, followed by stepwise analysis of the results.

Introduction: Interpersonal violent (IPV) experiences when they begin in childhood and continue in various forms during adulthood often lead to chronic post-traumatic stress disorder (PTSD) that is associated in multiple studies with hypocortisolism and lower percentage of methylation of the promoter region of the gene coding for the glucocorticoid receptor (NR3C1). This prospective, longitudinal study examined the relationship of NR3C1 methylation among mothers with IPV-related PTSD and their toddlers and then looked at the relationship of maternal NR3C1 methylation and child psychopathology at school age. Methods: Forty-eight mothers were evaluated for life-events history and post-traumatic stress disorder via structured clinical interview when their children were ages 12-42 months (mean age 26.7 months, SD 8.8). Their children's psychopathology in terms of internalizing symptoms and externalizing behaviors was evaluated using the Child Behavior Checklist at ages 5-9 years (mean age 7 years, SD 1.1). Percentage of methylation for the NR3C1 gene promoter region was assessed from DNA extracted from maternal and child saliva using bisulfite pyrosequencing. Data analysis involved parametric and non-parametric correlations and multiple linear and logistic regression modeling. Results: Logistic regression models using child NR3C1 methylation as the dependent variable and maternal NR3C1 methylation and PTSD group status as predictors, as well as the interaction indicated that all three of these significantly predicted child NR3C1 methylation. These findings remained significant when controlling for child age, sex and maternal child abuse history. Overall, maternal NR3C1 methylation when children were toddlers was negatively and significantly associated with child externalizing behavior severity at school age. Discussion: We found that correlations between mothers and their children of NR3C1 methylation levels overall and at all individual CpG sites of interest were significant only in the IPV-PTSD group. The latter findings support that NR3C1 methylation in mothers positively and statistically significantly correlates with NR3C1 methylation in their children only in presence of IPV-PTSD in the mothers. This maternal epigenetic signature with respect to this glucocorticoid receptor is significantly associated with child behavior that may well pose a risk for intergenerational transmission of violence and related psychopathology.

Ariane Paoloni-Giacobino,1,* François Luthi,2– 4,* Ludwig Stenz,1 Joane Le Carré,2,5 Philippe Vuistiner,2,5 Bertrand Léger2,5 1Medicine Faculty, Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland; 2Institute for Research in Rehabilitation, Clinique romande de réadaptation, Sion, Switzerland; 3Department of Musculoskeletal Rehabilitation, Clinique romande de réadaptation, Sion, Switzerland; 4Department of Physical Medicine and Rehabilitation, Orthopaedic Hospital, Lausanne University Hospital, Lausanne, Switzerland; 5Department of Medical Research, Clinique romande de réadaptation, Sion, Switzerland*These authors contributed equally to this workCorrespondence: Bertrand Léger Email bertrand.leger@crr-suva.chPurpose: The INTERMED instrument, which was developed to measure patient’s biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status.Patients and Methods: Fifty-eight chronic musculoskeletal pain patients (CMSP) were enrolled in the study. DNA was extracted from blood samples, the methylation levels of 13 CpG sites in the BDNF promoter were measured by pyrosequencing, and association studies with various patient parameters and the INTERMED scores were performed.Results: Interestingly, a negative correlation (− 0.40) was found between the total INTERMED scores and the average CpG methylation values of the BDNF gene, but no correlation was observed with the severity of pain, degree of anxiety, depression, or kinesiophobia and catastrophism. Moreover, the association was independent of age, sex and level of comorbidities.Conclusion: This result shows that CMSP, in association with its biopsychosocial context, epigenetically decreases the degree of methylation of the BDNF promoter and should therefore increase the level of BDNF transcription. It also suggests a role of the INTERMED tool to detect a relationship between the BPS complexity and the epigenetic control of a target gene. The possible upregulation of BDNF expression might be, at least in part, the signal for chronic pain-induced central sensitization (CS). This could partly explain why patients with a higher level of complexity feel more pain than those with lower complexity.Keywords: chronic pain, biopsychosocial complexity, BPS, INTERMED, brain-derived neurotrophic factor, BDNF, DNA methylation