Objectives: This study aimed to (a) evaluate the effects of Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) on immune-inflammatory biomarkers in patients with chronic low back pain and comorbid depression, and (b) explore whether these biomarkers and genetic polymorphisms in BDNF and FKBP5 predict treatment response. Methods: A total of 114 female participants (mean age=57.5 y) were randomized to a group-based therapy delivered via videoconference (ACT or BATD, both added to treatment-as-usual [TAU]) or TAU alone. Serum IL-6, CXCL-8, TNF-α, IL-1β, IL-10, high-sensitivity CRP, cortisol, vitamin D, and hair cortisol and cortisone were assessed at baseline and post-treatment, whereas BDNF and FKBP5 genotypes were assessed at baseline only. Clinical outcomes included pain interference, pain intensity, depressive symptoms, anxiety, stress, and pain catastrophizing. Results: Psychological interventions did not significantly change biomarker levels compared to TAU. However, ACT and BATD led to significant improvements in different clinical variables (e.g., pain interference, depressive symptomatology, anxiety, pain catastrophizing). Baseline biomarkers and FKBP5 genotype predicted treatment response, with some effects specific to ACT or BATD (e.g., cortisol, vitamin D) and others general across groups (e.g., hair cortisol, cortisone, CXCL-8); TNF-α and hs-CRP showed exploratory, descriptive associations with responder status. Discussion: While ACT and BATD improved clinical outcomes, their effects on immune-inflammatory biomarkers were not significant. Nevertheless, specific baseline biomarkers and genetic factors may serve as predictors of treatment response. These findings underscore the need to further explore the interaction between psychological therapies, biological processes, and individual variability in treatment outcomes.

OBJECTIVES:This study aimed to (a) evaluate the effects of Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) on immune-inflammatory biomarkers in patients with chronic low back pain and comorbid depression, and (b) explore whether these biomarkers and genetic polymorphisms in BDNF and FKBP5 predict treatment response. METHODS:A total of 114 female participants (mean age=57.5 y) were randomized to a group-based therapy delivered via videoconference (ACT or BATD, both added to treatment-as-usual [TAU]) or TAU alone. Serum IL-6, CXCL-8, TNF-α, IL-1β, IL-10, high-sensitivity CRP, cortisol, vitamin D, and hair cortisol and cortisone were assessed at baseline and post-treatment, whereas BDNF and FKBP5 genotypes were assessed at baseline only. Clinical outcomes included pain interference, pain intensity, depressive symptoms, anxiety, stress, and pain catastrophizing. RESULTS:Psychological interventions did not significantly change biomarker levels compared to TAU. However, ACT and BATD led to significant improvements in different clinical variables (e.g., pain interference, depressive symptomatology, anxiety, pain catastrophizing). Baseline biomarkers and FKBP5 genotype predicted treatment response, with some effects specific to ACT or BATD (e.g., cortisol, vitamin D) and others general across groups (e.g., hair cortisol, cortisone, CXCL-8); TNF-α and hs-CRP showed exploratory, descriptive associations with responder status. DISCUSSION:While ACT and BATD improved clinical outcomes, their effects on immune-inflammatory biomarkers were not significant. Nevertheless, specific baseline biomarkers and genetic factors may serve as predictors of treatment response. These findings underscore the need to further explore the interaction between psychological therapies, biological processes, and individual variability in treatment outcomes.

BACKGROUND AND HYPOTHESIS:Gene-by-environment (GxE) studies in psychosis have exclusively focused on negative exposures. However, evidence supports the resilience-enhancing effect of positive factors on psychosis outcome. The Differential Susceptibility (DS) model proposes that common genetic variants may confer not only disproportionate responsiveness to negative environments, but also greater sensitivity to positive, resilience-enhancing conditions. This study is the first to apply the DS model to the expression of subclinical psychosis, employing polygenic risk scores of environmental sensitivity (PRS-ES). PRS-ES were hypothesized to moderate, in a DS manner, associations between childhood adversity and psychosis, affective, and anxiety dimensions in young adults. An exploratory goal examined whether PRS for psychotic-like experiences (PRS-PLE) also showed DS patterns. STUDY DESIGN:PRS, schizotypy, PLE, depression, anxiety, and childhood adversity ratings were obtained for 197 nonclinical young adults. LEGIT software for testing competitive-confirmatory GxE models was employed. STUDY RESULTS:Results largely supported DS: Individuals high on PRS-ES showed increased subclinical psychosis, depression, and anxiety if they had experienced elevated childhood adversity, and lower symptoms if exposed to low levels of adversity as compared with those with low PRS-ES. Similarly, PRS-PLE moderated the effect of adversity on PLE, positive schizotypy, and depression following the DS model, but only PRS-ES moderation on PLE survived statistical correction. CONCLUSIONS:Our results suggest that genetic DS to the environment is relevant to psychosis, depression, and anxiety. Current debates on reconceptualization of genetic "risk" and resilience may benefit from this insight that support optimistic views on preventative efforts for early detection and intervention.

Most methodological Polygenic Risk Score (PRS)-related papers explain the laborious process of computing the PRS in great depth. Afterwards, as a last step, it is generally described that to test a possible association between a PRS and a trait of interest, an analysis through regression models (linear or logistic, depending on data type) should be carried out adjusting for covariates (e.g., sex, age, clinical information, or genetic ancestry-based Principal Components). When covariates are included, measurements such as the increment on the variance explained by the addition of the PRS to the model or the significance of the PRS term are usually reported. However, the association study between PRSs and a trait is a complex concern that requires proper modeling and analysis, since interactions and validation conditions represent crucial aspects. Even though excellent papers explain how to use and interpret the results obtained with such regression models, sometimes important information from the previously calculated PRS may be lost, partly due to the automation of analyses. With this guide, we intend to fill a gap in association studies between PRSs and a trait and to facilitate the analysis, obtaining statistically correct results. It contains a motivating real data case analyzed exhaustively to illustrate how to face a real analysis. Besides, it is accompanied by four examples, called Working Examples, which present different situations the researcher may encounter along with the R code for analyzing all these data sets and the corresponding application of the steps in this guide.

Research on gene-environment interactions in psychosis has been guided by diathesis-stress models, which emphasize the role of negative experiences. In contrast, the Differential Susceptibility (DS) model indicates that individuals differ in sensitivity to both adverse and supportive environments. This study replicates and expands an initial proof-of-concept DS study on psychosis by examining whether genetic sensitivity to the environment, indexed by polygenic scores of environmental sensitivity (PGS-ES) and psychotic-like experiences (PGS-PLE), moderated the impact of early-life positive and negative experiences on trans-syndromic outcomes, including subclinical psychotic features and positive mental health, in a DS manner. PGS and measures of early environmental, psychopathology, positive outcomes, and functioning were collected from 941 nonclinical young adults. A comprehensive factorial analysis of positive and negative environmental measures resulted in a general exposome score and four specific factors. A competitive-confirmatory approach examined DS patterns using LEGIT R package. Individuals with higher PGS-ES reported greater psychopathology, poorer functioning, and lower positive mental health outcomes when exposed to fewer positive experiences or poorer paternal parenting; but also exhibited less symptoms and more positive outcomes when exposed to supportive environments compared to individuals with lower PGS-ES. PGS-PLE only predicted psychopathology in a diathesis-stress manner. Findings support the trans-syndromic validity of the DS model, indicating that genetic susceptibility to the environment operated “for better and for worse” by impacting both ill and positive mental health. This highlights the importance of positive experiences and underscores the need to integrate risk and resilience models in psychosis.

Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Background According to the dimensional view of psychiatric disorders, psychosis is expressed as a continuum in the general population. However, the investigation of the putative genetic aetiological continuity between its clinical and subclinical phenotypes has yielded mixed results. We aimed to replicate previous findings regarding the association of polygenic risk for schizophrenia with subclinical traits (i.e., schizotypy traits and psychotic-like experiences), and to examine the role of sex in this association in a large nonclinical sample. Methods The Multidimensional Schizotypy Scale and the Community Assessment of Psychic Experiences were assessed in 919 nonclinical participants. Polygenic Risk Scores for schizophrenia (SZ-PRSs) were computed using the PRS-CS method based on the latest genome-wide association study of schizophrenia. Summary statistics derived from the total GWAS sample and stratified by sex were used. Linear regression analyses tested the associations of the SZ-PRSs with the psychometric variables, both in the total sample and by sex. Results No associations were found between the SZ-PRSs and the positive, negative or disorganized dimensions of schizotypy in the total sample. Likewise, no associations were found with psychotic-like experiences. However, the sex-stratified analyses revealed a male-specific association with positive schizotypy. Similar results were obtained with the PRSs derived from the sex-stratified summary statistics. Discussion Our results are consistent with the lack of clear evidence of an association between SZ common genetic risk and its subclinical phenotypes. Nevertheless, the male-specific association found suggests that this PRS might explain better the male phenotype, as reported in previous studies. Future studies should put a focus on the role of sex in this association to unravel its sex specificities.

BACKGROUND:Bariatric surgery (BS) is currently the most effective long-term treatment of severe obesity. However, the interindividual variability observed in surgical outcomes suggests a moderating effect of several factors, including individual genetic background. This study aimed to investigate the contribution of the genetic architecture of body mass index (BMI) to the variability in weight loss outcomes after BS. METHODS:A total of 106 patients with severe obesity who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy were followed up for 5 years. Changes in BMI (BMIchange) and percentage of total weight loss (%TWL) were evaluated during the postoperative period. Polygenic risk scores (PRSs), including 50 genetic variants, were calculated for each participant to determine their genetic risk of high BMI based on a previous genome-wide association study. Generalized estimating equation models were used to study the role of the individual's polygenic score and other factors on BMIchange and %TWL in the long term after surgery. RESULTS:This study found an effect of the polygenic score on %TWL and BMIchange, in which patients with lower scores had better outcomes after surgery than those with higher scores. Furthermore, when analyzing only patients who underwent RYGB, the results were replicated, showing greater weight loss after surgery for patients with lower polygenic scores. DISCUSSION:Our results indicate that genetic background assessed with PRSs, along with other individual factors, such as biological sex, age, and preoperative BMI, has an effect on BS outcomes and could represent a useful tool for estimating surgical outcomes in advance.

Objective Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA®) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. Methods A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. Conclusions This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders.

Background: Obesity is a polygenic multifactorial disease. Recent genome-wide association studies have identified several common loci associated with obesity-related phenotypes. Bariatric surgery (BS) is the most effective long-term treatment for patients with severe obesity. The huge variability in BS outcomes between patients suggests a moderating effect of several factors, including the genetic architecture of the patients. Objective: To examine the role of a genetic risk score (GRS) based on 7 polymorphisms in 5 obesity-candidate genes (FTO, MC4R, SIRT1, LEP, and LEPR) on weight loss after BS. Setting: University hospital in Spain. Methods: We evaluated a cohort of 104 patients with severe obesity submitted to BS (Roux-en-Y gastric bypass or sleeve gastrectomy) followed up for >60 months (lost to follow-up, 19.23%). A GRS was calculated for each patient, considering the number of carried risk alleles for the analyzed genes. During the postoperative period, the percentage of excess weight loss total weight loss and changes in body mass index were evaluated. Generalized estimating equation models were used for the prospective analysis of the variation of these variables in relation to the GRS. Results: The longitudinal model showed a significant effect of the GRS on the percentage of excess weight loss (P = 1.5 x 10(-5)), percentage of total weight loss (P = 3.1 x 10(-8)), and change in body mass index (P = 7.8 x 10(-16)) over time. Individuals with a low GRS seemed to experience better outcomes at 24 and 60 months after surgery than those with a higher GRS. Conclusion: The use of the GRS in considering the polygenic nature of obesity seems to be a useful tool to better understand the outcome of patients with obesity after BS.

Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in the general population often broadly referred to as schizotypy. However, it is still poorly understood how these traits overlap genetically with the disorder. We investigated whether polygenic risk for SZ is associated with these disorder-related phenotypes (schizotypy, psychotic-like experiences, and subclinical psychopathology) in a sample of 253 non-clinically identified participants. Polygenic risk scores (PRSs) were constructed based on the latest SZ genome-wide association study using the PRS-CS method. Their association with self-report and interview measures of SZ-related traits was tested. No association with either schizotypy or psychotic-like experiences was found. However, we identified a significant association with the Motor Change subscale of the Comprehensive Assessment of At-Risk Mental States (CAARMS) interview. Our results indicate that the genetic overlap of SZ with schizotypy and psychotic-like experiences is less robust than previously hypothesized. The relationship between high PRS for SZ and motor abnormalities could reflect neurodevelopmental processes associated with psychosis proneness and SZ.

Severe obesity (SO) can accelerate atherosclerosis and the onset of acute cardiovascular events. The diagnosis of atherosclerosis in the context of a high body mass index (BMI) can be challenging, making the identification of biomarkers clinically relevant. We aimed to assess the usefulness of irisin as a biomarker for subclinical atherosclerosis in participants with SO. This prospective observational study included 61 participants undergoing bariatric surgery for SO, defined as a BMI >40 kg/m2 or >35 kg/m2 with at least one comorbidity. Atherosclerotic plaques were detected by ultrasound. Plasma samples were obtained 1 month before and at 6 and 12 months after bariatric surgery to measure irisin by ELISA. Additionally, subcutaneous samples of adipose tissue were taken and genotyped to identify irisin polymorphism rs3480. Irisin levels were positively correlated with BMI (r = 0.23, p = 0.0064), negatively correlated with atheroma-related parameters (e.g., carotid intima-media thickness), and lower in subjects with atheroma (p < 0.0002). Irisin also showed good overall accuracy for discriminating plaque presence (AUC, 0.81; 95% CI, 0.6956–0.9156). However, the rs3480 polymorphism correlated with neither the irisin levels nor the presence of atheromas. Iirisin could identify subclinical atherosclerosis in SO and might facilitate clinical diagnosis.

Schizophrenia is a heterogeneous and severe psychotic disorder. Epidemiological findings have suggested that the exposure to infectious agents such as Toxoplasma gondii (T. gondii) is associated with an increased risk for schizophrenia. On the other hand, there is evidence involving the catechol-O-methyltransferase (COMT) Val105/158Met polymorphism in the aetiology of schizophrenia since it alters the dopamine metabolism. A case–control study of 141 patients and 142 controls was conducted to analyse the polymorphism, the prevalence of anti-T. gondii IgG, and their interaction on the risk for schizophrenia. IgG were detected by ELISA, and genotyping was performed with TaqMan Real-Time PCR. Although no association was found between any COMT genotype and schizophrenia, we found a significant association between T. gondii seropositivity and the disorder (χ2 = 11.71; p-value < 0.001). Furthermore, the risk for schizophrenia conferred by T. gondii was modified by the COMT genotype, with those who had been exposed to the infection showing a different risk compared to that of nonexposed ones depending on the COMT genotype (χ2 for the interaction = 7.28, p-value = 0.007). This study provides evidence that the COMT genotype modifies the risk for schizophrenia conferred by T. gondii infection, with it being higher in those individuals with the Met/Met phenotype, intermediate in heterozygous, and lower in those with the Val/Val phenotype.

Adequate levels offolate are crucial for human development. MTHFR (Methylene tetrahydrofolate reductase) is involved in the metabolism of folic acid and other B vitamins. The aim of this work is to examine the allele frequency and haplotype distribution of MTHFR-C677T and MTHFR-A1298C polymorphisms in two independent samples (North-East Spanish and North-Western Siberia). The degree of population differentiation and signatures of positive selection were also examined in 18 world populations. The samples comprised 623 Spanish individuals and 172 Ob-Ugric people (Khanty and Mansi). The Spanish sample showed 44% individuals with 30% reduced enzyme activity, and 16% people with 70% reduced activity; whereas the Khanty sample revealed only 3% people with 70% reduced activity. In the 18 populations screened, we found significant South to North clines for SNPs and haplotypes. Overall, we failed to detect any traces of positive selection. The high frequency of people with reduced MTHFR enzyme activity in Spain highlights the need for diets rich in folate and folic acid supplementation in some groups. The low frequency of individuals with reduced enzymatic activity among the Khanty together with their traditional diet indicates a protective combination against pathologies related to folic acid deficiencies.