Journal: Translational psychiatry
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.
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.
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.
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.
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.
Elevated levels of prenatal testosterone may increase the risk for autism spectrum conditions (autism). Given that polycystic ovary syndrome (PCOS) is also associated with elevated prenatal testosterone and its precursor sex steroids, a hypothesis from the prenatal sex steroid theory is that women with PCOS should have elevated autistic traits and a higher rate of autism among their children. Using electronic health records obtained from the Clinical Practice Research Datalink (CPRD) in the UK between 1990 and 2014, we conducted three matched case-control studies. Studies 1 and 2 examined the risk of PCOS in women with autism (n = 971) and the risk of autism in women with PCOS (n = 26,263), respectively, compared with matched controls. Study 3 examined the odds ratio (OR) of autism in first-born children of women with PCOS (n = 8588), matched to 41,127 controls. In Studies 1 and 2 we found increased prevalence of PCOS in women with autism (2.3% vs. 1.1%; unadjusted OR: 2.01, 95% CI: 1.22-3.30) and elevated rates of autism in women with PCOS (0.17% vs. 0.09%, unadjusted OR: 1.94 CI: 1.37-2.76). In Study 3 we found the odds of having a child with autism were significantly increased, even after adjustment for maternal psychiatric diagnoses, obstetric complications, and maternal metabolic conditions (unadjusted OR: 1.60, 95% CI: 1.28-2.00; adjusted OR: 1.35, 95% CI: 1.06-1.73). These studies provide further evidence that women with PCOS and their children have a greater risk of autism.
Obesity is associated with an increased risk of depression. The aim of the present study was to investigate whether obesity is a causative factor for the development of depression and what is the molecular pathway(s) that link these two disorders. Using lipidomic and transcriptomic methods, we identified a mechanism that links exposure to a high-fat diet (HFD) in mice with alterations in hypothalamic function that lead to depression. Consumption of an HFD selectively induced accumulation of palmitic acid in the hypothalamus, suppressed the 3', 5'-cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and increased the concentration of free fatty acid receptor 1 (FFAR1). Deficiency of phosphodiesterase 4A (PDE4A), an enzyme that degrades cAMP and modulates stimulatory regulative G protein (Gs)-coupled G protein-coupled receptor signaling, protected animals either from genetic- or dietary-induced depression phenotype. These findings suggest that dietary intake of saturated fats disrupts hypothalamic functions by suppressing cAMP/PKA signaling through activation of PDE4A. FFAR1 inhibition and/or an increase of cAMP signaling in the hypothalamus could offer potential therapeutic targets to counteract the effects of dietary or genetically induced obesity on depression.
The identification of brain-targeted autoantibodies in children with autism spectrum disorder (ASD) raises the possibility of autoimmune encephalopathy (AIE). Intravenous immunoglobulin (IVIG) is effective for AIE and for some children with ASD. Here, we present the largest case series of children with ASD treated with IVIG. Through an ASD clinic, we screened 82 children for AIE, 80 of them with ASD. IVIG was recommended for 49 (60%) with 31 (38%) receiving the treatment under our care team. The majority of parents (90%) reported some improvement with 71% reporting improvements in two or more symptoms. In a subset of patients, Aberrant Behavior Checklist (ABC) and/or Social Responsiveness Scale (SRS) were completed before and during IVIG treatment. Statistically significant improvement occurred in the SRS and ABC. The antidopamine D2L receptor antibody, the anti-tubulin antibody and the ratio of the antidopamine D2L to D1 receptor antibodies were related to changes in the ABC. The Cunningham Panel predicted SRS, ABC, parent-based treatment responses with good accuracy. Adverse effects were common (62%) but mostly limited to the infusion period. Only two (6%) patients discontinued IVIG because of adverse effects. Overall, our open-label case series provides support for the possibility that some children with ASD may benefit from IVIG. Given that adverse effects are not uncommon, IVIG treatment needs to be considered cautiously. We identified immune biomarkers in select IVIG responders but larger cohorts are needed to study immune biomarkers in more detail. Our small open-label exploratory trial provides evidence supporting a neuroimmune subgroup in patients with ASD.
Music has been identified as a strength in people with Autism Spectrum Disorder; however, there is currently no neuroscientific evidence supporting its benefits. Given its universal appeal, intrinsic reward value and ability to modify brain and behaviour, music may be a potential therapeutic aid in autism. Here we evaluated the neurobehavioural outcomes of a music intervention, compared to a non-music control intervention, on social communication and brain connectivity in school-age children (ISRCTN26821793). Fifty-one children aged 6-12 years with autism were randomized to receive 8-12 weeks of music (n = 26) or non-music intervention (n = 25). The music intervention involved use of improvisational approaches through song and rhythm to target social communication. The non-music control was a structurally matched behavioural intervention implemented in a non-musical context. Groups were assessed before and after intervention on social communication and resting-state functional connectivity of fronto-temporal brain networks. Communication scores were higher in the music group post-intervention (difference score = 4.84, P = .01). Associated post-intervention resting-state brain functional connectivity was greater in music vs. non-music groups between auditory and subcortical regions (z = 3.94, P < .0001) and auditory and fronto-motor regions (z = 3.16, P < .0001). Post-intervention brain connectivity was lower between auditory and visual regions in the music compared to the non-music groups, known to be over-connected in autism (z = 4.01, P < .00001). Post-intervention brain connectivity in the music group was related to communication improvement (z = 3.57, P < .0001). This study provides the first evidence that 8-12 weeks of individual music intervention can indeed improve social communication and functional brain connectivity, lending support to further investigations of neurobiologically motivated models of music interventions in autism.
Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the “missing heritability” between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.