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Journal: Translational psychiatry

359

Empathy is the ability to recognize and respond to the emotional states of other individuals. It is an important psychological process that facilitates navigating social interactions and maintaining relationships, which are important for well-being. Several psychological studies have identified difficulties in both self-report and performance-based measures of empathy in a range of psychiatric conditions. To date, no study has systematically investigated the genetic architecture of empathy using genome-wide association studies (GWAS). Here we report the results of the largest GWAS of empathy to date using a well-validated self-report measure of empathy, the Empathy Quotient (EQ), in 46,861 research participants from 23andMe, Inc. We identify 11 suggestive loci (P < 1 × 10-6), though none were significant at P < 2.5 × 10-8after correcting for multiple testing. The most significant SNP was identified in the non-stratified analysis (rs4882760; P = 4.29 × 10-8), and is an intronic SNP in TMEM132C. The EQ had a modest but significant narrow-sense heritability (0.11 ± 0.014; P = 1.7 × 10-14). As predicted, based on earlier work, we confirmed a significant female advantage on the EQ (P < 2 × 10-16, Cohen's d = 0.65). We identified similar SNP heritability and high genetic correlation between the sexes. Also, as predicted, we identified a significant negative genetic correlation between autism and the EQ (rg= -0.27 ± 0.07, P = 1.63 × 10-4). We also identified a significant positive genetic correlation between the EQ and risk for schizophrenia (rg= 0.19 ± 0.04; P = 1.36 × 10-5), risk for anorexia nervosa (rg= 0.32 ± 0.09; P = 6 × 10-4), and extraversion (rg= 0.45 ± 0.08; 5.7 × 10-8). This is the first GWAS of self-reported empathy. The results suggest that the genetic variations associated with empathy also play a role in psychiatric conditions and psychological traits.

Concepts: Psychology, Genetics, Greek loanwords, Anorexia nervosa, Eating disorders, Genome-wide association study, Correlation and dependence, Emotion

168

Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69-1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

157

The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for ‘genome-wide significance’. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9-24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.

Concepts: Gene, Genetics, Signal transduction, Action potential, Epilepsy, Absence seizure, Potassium channel, Neurological disorders

137

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

136

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.

Concepts: Positron emission tomography, Serotonin, Fluvoxamine, Antidepressant, Selective serotonin reuptake inhibitor, Major depressive disorder, Sertraline, Obsessive–compulsive disorder

105

Offspring of persons exposed to childhood abuse are at higher risk of neurodevelopmental and physical health disparities across the life course. Animal experiments have indicated that paternal environmental stressors can affect sperm DNA methylation and gene expression in an offspring. Childhood abuse has been associated with epigenetic marks in human blood, saliva, and brain tissue, with statistically significant methylation differences ranging widely. However, no studies have examined the association of childhood abuse with DNA methylation in gametes. We examined the association of childhood abuse with DNA methylation in human sperm. Combined physical, emotional, and sexual abuse in childhood was characterized as none, medium, or high. DNA methylation was assayed in 46 sperm samples from 34 men in a longitudinal non-clinical cohort using HumanMethylation450 BeadChips. We performed principal component analysis and examined the correlation of principal components with abuse exposure. Childhood abuse was associated with a component that captured 6.2% of total variance in DNA methylation (p < 0.05). Next, we investigated the regions differentially methylated by abuse exposure. We identified 12 DNA regions differentially methylated by childhood abuse, containing 64 probes and including sites on genes associated with neuronal function (MAPT, CLU), fat cell regulation (PRDM16), and immune function (SDK1). We examined adulthood health behaviors, mental health, and trauma exposure as potential mediators of an association between abuse and DNAm, and found that mental health and trauma exposure partly mediated the association. Finally, we constructed a parsimonious epigenetic marker for childhood abuse using a machine learning approach, which identified three probes that predicted high vs. no childhood abuse in 71% of participants. Our results suggested that childhood abuse is associated with sperm DNA methylation, which may have implications for offspring development. Larger samples are needed to identify with greater confidence specific genomic regions differentially methylated by childhood abuse.

101

No studies have examined the relationship between endogenous polyunsaturated fatty acids (PUFAs) levels and treatment response to PUFAs. We conducted a 12-week, double-blind, placebo-controlled trial comparing the effects of high-dose eicosapentaenoic acid (EPA, 1.2 g) and placebo on cognitive function (continuous performance test) in n = 92 youth (age 6-18-years-old) with Attention Deficit Hyperactivity Disorder (ADHD). Blood erythrocytes PUFAs were measured before and after treatment, to examine the effects of baseline endogenous EPA levels on treatment response and the effects of EPA treatment on PUFAs levels. Secondary measures included other ADHD symptoms, emotional symptoms, and levels of plasma high-sensitivity c-reactive protein (hs-CRP) and brain-derived neurotrophic factor (BDNF). Overall, EPA group improved more than placebo group on focused attention (variability, Effect size (ES) = 0.38, p = 0.041); moreover, within youth with the lowest baseline endogenous EPA levels, EPA group improved more than placebo group in another measure of focused attention (hit reaction time, HRT, ES = 0.89, p = 0.015) and in vigilance (HRT interstimulus interval changes, HRTISIC, ES = 0.83, p = 0.036). Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. EPA increased blood erythrocytes EPA by 1.6-fold but not DHA levels, and did not affect hs-CRP and BDNF plasma levels. In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.

93

Exposure of male mice to early life stress alters the levels of specific sperm miRNAs that promote stress-associated behaviors in their offspring. To begin to evaluate whether similar phenomena occur in men, we searched for sperm miRNA changes that occur in both mice and men exposed to early life stressors that have long-lasting effects. For men, we used the Adverse Childhood Experience (ACE) questionnaire. It reveals the degree of abusive and/or dysfunctional family experiences when young, which increases risks of developing future psychological and physical disorders. For male mice, we used adolescent chronic social instability (CSI) stress, which not only enhances sociability defects for >1 year, but also anxiety and defective sociability in female offspring for multiple generations through the male lineage. Here we found a statistically significant inverse correlation between levels of multiple miRNAs of the miR-449/34 family and ACE scores of Caucasian males. Remarkably, we found members of the same sperm miRNA family are also reduced in mice exposed to CSI stress. Thus, future studies should be designed to directly test whether reduced levels of these miRNAs could be used as unbiased indicators of current and/or early life exposure to severe stress. Moreover, after mating stressed male mice, these sperm miRNA reductions persist in both early embryos through at least the morula stage and in sperm of males derived from them, suggesting these miRNA changes contribute to transmission of stress phenotypes across generations. Since offspring of men exposed to early life trauma have elevated risks for psychological disorders, these findings raise the possibility that a portion of this risk may be derived from epigenetic regulation of these sperm miRNAs.

82

Western societies notice an increasing interest in plant-based eating patterns such as vegetarian and vegan, yet potential effects on the body and brain are a matter of debate. Therefore, we systematically reviewed existing human interventional studies on putative effects of a plant-based diet on the metabolism and cognition, and what is known about the underlying mechanisms. Using the search terms “plant-based OR vegan OR vegetarian AND diet AND intervention” in PubMed filtered for clinical trials in humans retrieved 205 studies out of which 27, plus an additional search extending the selection to another five studies, were eligible for inclusion based on three independent ratings. We found robust evidence for short- to moderate-term beneficial effects of plant-based diets versus conventional diets (duration ≤ 24 months) on weight status, energy metabolism and systemic inflammation in healthy participants, obese and type-2 diabetes patients. Initial experimental studies proposed novel microbiome-related pathways, by which plant-based diets modulate the gut microbiome towards a favorable diversity of bacteria species, yet a functional “bottom up” signaling of plant-based diet-induced microbial changes remains highly speculative. In addition, little is known, based on interventional studies about cognitive effects linked to plant-based diets. Thus, a causal impact of plant-based diets on cognitive functions, mental and neurological health and respective underlying mechanisms has yet to be demonstrated. In sum, the increasing interest for plant-based diets raises the opportunity for developing novel preventive and therapeutic strategies against obesity, eating disorders and related comorbidities. Still, putative effects of plant-based diets on brain health and cognitive functions as well as the underlying mechanisms remain largely unexplored and new studies need to address these questions.

71

Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.