Interaction between PTSD-PRS and trauma affects PTSD likelihood in women victims of sexual assault.

OBJECTIVE: Post-traumatic stress disorder (PTSD) is triggered by traumatic events, but genetic vulnerability and a history of childhood trauma are additional factors that may increase the risk of PTSD. Thus, our study focused on exploring the interaction between genetic susceptibility, as assessed by polygenic risk score (PRS), and traumatic events. METHODS: We evaluated 68 women with PTSD who had been sexually assaulted and 63 healthy controls without a history of sexual assault. DNA was genotyped using the Infinium Global Screening Array (Illumina), and PRS analysis was performed using PRSice. Furthermore, logistic regression models were employed to examine the interaction between childhood trauma, traumatic life events, and PTSD-PRS and how they contribute to the risk of developing PTSD. RESULTS: We found a significant association between PRS, childhood trauma (p = 0.03; OR = 1.241), and PTSD. Additionally, an interaction was observed between PRS, traumatic life events, and childhood trauma, particularly relating to physical and emotional neglect (p = 0.028; OR = 1.010). When examining neglect separately, we found a modest association between emotional neglect and PTSD (p = 0.014; OR = 1.086). CONCLUSIONS: Our findings highlight the importance of considering genetic vulnerability and traumatic experiences in understanding the etiology of PTSD.

Lifetime cannabis use and childhood trauma associated with CNR1 genetic variants increase the risk of psychosis: findings from the STREAM study.

OBJECTIVES: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. METHODS: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. RESULTS: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. CONCLUSION: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use.

Alterations in microRNA of extracellular vesicles associated with major depression, attention-deficit/hyperactivity and anxiety disorders in adolescents.

Extracellular vesicles (EVs) are present in numerous peripheral bodily fluids and function in critical biological processes, including cell-to-cell communication. Most relevant to the present study, EVs contain microRNAs (miRNAs), and initial evidence from the field indicates that miRNAs detected in circulating EVs have been previously associated with mental health disorders. Here, we conducted an exploratory longitudinal and cross-sectional analysis of miRNA expression in serum EVs from adolescent participants. We analyzed data from a larger ongoing cohort study, evaluating 116 adolescent participants at two time points (wave 1 and wave 2) separated by three years. Two separate data analyses were employed: A cross-sectional analysis compared individuals diagnosed with Major Depressive Disorder (MDD), Anxiety disorders (ANX) and Attention deficit/Hyperactivity disorder (ADHD) with individuals without psychiatric diagnosis at each time point. A longitudinal analysis assessed changes in miRNA expression over time between four groups showing different diagnostic trajectories (persistent diagnosis, first incidence, remitted and typically developing/control). Total EVs were isolated, characterized by size distribution and membrane proteins, and miRNAs were isolated and sequenced. We then selected differentially expressed miRNAs for target prediction and pathway enrichment analysis. In the longitudinal analysis, we did not observe any statistically significant results. In the cross-sectional analysis: in the ADHD group, we observed an upregulation of miR-328-3p at wave 1 only; in the MDD group, we observed a downregulation of miR-4433b-5p, miR-584-5p, miR-625-3p, miR-432-5p and miR-409-3p at wave 2 only; and in the ANX group, we observed a downregulation of miR-432-5p, miR-151a-5p and miR-584-5p in ANX cases at wave 2 only. Our results identified previously observed and novel differentially expressed miRNAs and their relationship with three mental health disorders. These data are consistent with the notion that these miRNAs might regulate the expression of genes associated with these traits in genome-wide association studies. The findings support the promise of continued identification of miRNAs contained within peripheral EVs as biomarkers for mental health disorders.

Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis.

Rotator cuff tears (RCT) is a multifactorial disease with genetic factors contributing for the disease etiology. We hypothesized that genetic variants in genes involved in extracellular matrix (ECM) homeostasis may alter susceptibility to RCT. We evaluated 20 polymorphisms of genes involved in ECM homeostasis in 211 cases of full-thickness tears of the supraspinatus (Nfemales = 130; Nmales = 81) and 567 age-matched controls (Nfemales = 317; Nmales = 250). Multivariate logistic regressions were carried out with age, gender, genetic ancestry (based on the analysis of 61 biallelic short insertion/deletion polymorphisms), and common co-morbidities (diabetes, dyslipidemia, and smoking habits) as covariates. We observed that carriers of the rare allele of both studied variants of TGFB1, as well as their G/A (rs1800470/rs1800469) haplotype, were less susceptible to RCT (p < 0.05). In contrast, carriers of the G allele of MMP9 rs17576 (p = 0.014) or G/G haplotype (rs17576/rs17577; p < 0.001) had an increased risk for tendon tears. The presence of the T allele of MMP2 rs2285053 (p = 0.033), the T allele of MMP3 rs679620 (p = 0.024), and the TT-genotype of TIMP2 rs2277698 (p = 0.01) was associated with susceptibility to tears, especially in females. In males, the A allele of COL5A1 rs3196378 (p = 0.032) and the G allele of TGFBR1 rs1590 (p = 0.039) were independent risk factors for RCT. The C/T COL5A1 (rs3196378/rs11103544) haplotype was associated with a reduced risk of tears in males (p = 0.03). In conclusion, we identified the genetic variants associated with RCT susceptibility, thereby reinforcing the role of genes involved in the structure and homeostasis of the ECM of tendons in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:192-201, 2020.

The interaction between polygenic risk score and trauma affects the likelihood of post-traumatic stress disorder in female victims of sexual assault

Objective: Post-traumatic stress disorder (PTSD) is triggered by traumatic events, but genetic vulnerability and a history of childhood trauma may also increase the risk of PTSD onset. Thus, we investigated the interaction between genetic susceptibility according to polygenic risk score (PRS), and traumatic events. Methods: We evaluated 68 women with PTSD who had been sexually assaulted and 63 healthy controls with no history of sexual assault. DNA was genotyped using the Infinium Global Screening Array (Illumina, San Diego, CA, USA), and PRS analysis was performed using PRSice. Logistic regression models were also used to determine the interaction between childhood trauma, traumatic life events, and PRS and how they contribute to PTSD risk. Results: We found a significant association between PRS, childhood trauma (p = 0.03; OR = 1.241), and PTSD. There was also an interaction between PRS, traumatic life events, and childhood trauma, particularly physical and emotional neglect (p = 0.028; OR = 1.010). When examining neglect separately, we found a modest association between emotional neglect and PTSD (p = 0.014; OR = 1.086). Conclusion: Our findings highlight the importance of considering genetic vulnerability and traumatic experiences in understanding the etiology of PTSD.

Genetic variants involved in extracellular matrix homeostasis play a role in the susceptibility to frozen shoulder: A case-control study.

Frozen shoulder is a condition of loss of active and passive motion as result of inflammatory contracture and fibrosis of the joint capsule. We hypothesize that genetic variants in genes involved in these processes such as genes that play a role in extracellular matrix homeostasis (collagens, glycoproteins, genes involved in TGFß signaling, and metalloproteinases and its inhibitors) may contribute to the susceptibility to frozen shoulder. We evaluated eighteen SNPs of genes involved in extracellular matrix homeostasis in 186 cases (Nfemales = 114; Nmales = 72) of frozen shoulder and 600 age-matched controls (Nfemales = 308; Nmales = 292). Multivariate logistic regressions were carried out with age, gender, genetic ancestry, and common comorbidities as covariates. Carriers of the C allele of MMP13 rs2252070 and G/G MMP9 (rs17576 A>G/rs17577 G>A) haplotype may have an increased risk of frozen shoulder (p = 0.002, OR = 1.64, 95%CI = 1.20-2.26, and p = 0.046, OR = 1.40, 95%CI = 1.01-1.95, respectively), especially in females (p = 0.005, OR = 1.91, 95%CI = 1.22-2.99, and p = 0.046, OR = 1.59, 95%CI = 1.01-2.51, respectively). In females, the G allele of MMP9 rs17576 tended to contribute to the susceptibility to the studied disease (p = 0.05, OR = 1.51, 95%CI = 0.97-2.33). In contrast, the presence of the C allele of TGFB1 rs1800470 seems to be associated with a reduced risk (p = 0.04, OR = 0.47, 95%CI = 0.23-0.96) while the GG-genotype of TGFBR1 rs1590 was associated with increased risk (p = 0.027, OR = 4.11, 95%CI = 1.17-14.38) to frozen shoulder development in males. Thus, we identified genetic variants that were independent risk factors that can aid in the risk assessment of frozen shoulder reinforcing the involvement of MMP and TGFß signaling in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of CNR1 genetic variants: findings from the STREAM study

Objectives: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. Methods: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. Results: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. Conclusion: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use.

Autonomic response of older women to the submaximal effort in the six-minute walk test: a cross-sectional study / Resposta autonômica de mulheres idosas ao esforço submáximo do teste de caminhada de seis minutos: um estudo transversal / Respuesta autonómica de ancianas al esfuerzo submáximo en la prueba de paso de seis minutos: un estudio transversal

ABSTRACT This cross-sectional study aimed to evaluate the autonomic response of older women in the six-minute walk test. In total, 32 women aged 60 years or older without a diagnosed health problem were evaluated during the six-minute walk test. To monitor the autonomic response, the following variables were considered: heart rate, systolic and diastolic blood pressure, respiratory rate, and perceived exertion. These variables were compared during rest, effort, and recovery. This study also sought a correlation between autonomic function variables and performance in the test and perceived exertion. Results showed that the effort made by older women in the six-minute walk test induces an autonomic response resulting in increased heart rate and systolic and diastolic blood pressure; however, the respiratory rate remained unchanged during the test. Diastolic blood pressure remained high during recovery. No correlation was found neither between perceived exertion and cardiovascular physiological response nor between distance covered and variation of the autonomic response or level of physical conditioning. Therefore, the effort spent in the six-minute walk test promotes an autonomic response in older women, increasing cardiovascular stress without increasing ventilation. In this context, the Borg scale was not representative of cardiovascular stress during the test.

RESUMO O objetivo deste estudo foi investigar a resposta autonômica de idosas ao esforço do teste de caminhada de 6 minutos (TC6M). Realizou-se um estudo transversal a partir da avaliação de 32 idosas, sem problemas de saúde diagnosticados, com 60 anos ou mais, durante o TC6M. Para o monitoramento da resposta autonômica, foram consideradas as seguintes variáveis: frequência cardíaca, pressão arterial sistólica e diastólica, frequência respiratória e percepção de esforço. Essas variáveis foram comparadas durante o período de repouso, esforço e recuperação. Buscou-se também correlação entre as variáveis da função autonômica e o desempenho no teste e a percepção de esforço. Os resultados demonstraram que o esforço gerado no TC6M induz uma resposta autonômica que leva ao aumento da frequência cardíaca e da pressão arterial sistólica e diastólica em mulheres, porém a frequência respiratória permaneceu inalterada durante o teste. A pressão arterial diastólica permaneceu elevada durante a recuperação. Não houve correlação entre a percepção de esforço e a resposta fisiológica cardiovascular apresentada, nem entre a distância percorrida e a variação da resposta autonômica ou o nível de condicionamento físico. Concluiu-se que o esforço despendido no TC6M promove uma resposta autonômica em idosas, intensificando o estresse cardiovascular sem aumentar a ventilação. Nesse contexto, a escala de Borg não foi representativa do estresse cardiovascular durante o teste.

RESUMEN El objetivo de este estudio fue investigar la respuesta autonómica de ancianas al esfuerzo en la prueba de paso de 6 minutos (6MWT). Se realizó un estudio transversal con la participación de 32 ancianas, de 60 años o más, sin problemas de salud diagnosticados durante la 6MWT. Para monitorear la respuesta autonómica, se consideraron las siguientes variables: frecuencia cardíaca, presión arterial sistólica y diastólica, frecuencia respiratoria y esfuerzo percibido. Se compararon estas variables durante el período de reposo, esfuerzo y recuperación. También se buscó una correlación entre las variables de función autonómica y rendimiento en la prueba y el esfuerzo percibido. Los resultados mostraron que el esfuerzo producido en la 6MWT genera una respuesta autonómica que conduce a un aumento de la frecuencia cardíaca y de la presión arterial sistólica y diastólica en las mujeres, pero la frecuencia respiratoria se mantuvo sin cambios durante la prueba. La presión arterial diastólica se mantuvo alta durante el período de recuperación. No hubo correlación entre el esfuerzo percibido y la respuesta fisiológica cardiovascular presentada, tampoco entre la distancia recorrida y la variación de la respuesta autonómica o el nivel de condicionamiento físico. Se concluyó que el esfuerzo realizado en la 6MWT generó una respuesta autonómica en las ancianas al intensificar el estrés cardiovascular pero sin aumentar la ventilación. En este contexto, la escala de Borg no fue significativa para el estrés cardiovascular durante la prueba.

Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears.

Rotator cuff tear is a common orthopedic condition. Metalloproteinases (MMP) and their inhibitors (TIMP) seem to play a role in the development of joint injuries and in the failure of tissue healing. However, the mechanisms of regulation of gene expression in tendons are still unknown. Epigenetic mechanisms, such as DNA methylation and microRNAs regulation, are involved in the dynamic control of gene expression. Here, the mRNA expression and DNA methylation status of MMPs (MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14) and TIMPs (TIMP1-3) and the expression of miR-29 family members in ruptured supraspinatus tendons were compared with non-injured tendons of individuals without this lesion. Additionally, the gene expression and methylation status at the edge of the ruptured tendon were compared with macroscopically non-injured rotator cuff tendon samples from the anterior and posterior regions of patients with tendon tears. Moreover, the possible associations between the molecular alterations and the clinical and histologic characteristics were investigated. Dysregulated expression and DNA methylation of MMP and TIMP genes were found across the rotator cuff tendon samples of patients with supraspinatus tears. These alterations were influenced at least in part by age at surgery, sex, smoking habit, tear size, and duration of symptoms. Alterations in the studied MMP and TIMP genes may contribute to the presence of microcysts, fissures, necrosis, and neovascularization in tendons and may thus be involved in the tendon healing process. In conclusion, MMPs and their inhibitors are regulated by epigenetic modifications and may play a role in rotator cuff tears.