Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

Early in their course, cognitive deficits are present in all psychotic disorders but are most severe and pervasive in schizophrenia and least pervasive in bipolar disorder and mania.

Background. Against a backdrop of increasing research, clinical and taxonomic attention in non-suicidal self-injury (NSSI), evidence suggests a link between NSSI and eating disorders (ED). The frequency estimates of NSSI in ED vary widely. Little is known about the sources of this variation, and no meta-analysis has quantified the association between ED and NSSI.Method. Using random-effects meta-analyses, meta-regression analyses, and 1816-6466 unique participants with various ED, we estimated the weighted average percentage of individuals with ED, those with anorexia nervosa (AN) and those with bulimia nervosa (BN) who are reported to have a lifetime history of NSSI across studies. We further examined predictors of NSSI in ED.Results. The weighted average percentage of patients with a lifetime history of NSSI was 27.3% [95% confidence interval (CI) 23.8-31.0%] for ED, 21.8% (95% CI 18.5-25.6%) for AN, and 32.7% (95% CI 26.9-39.1%) for BN. The difference between BN and AN was statistically significant [odds ratio (OR) 1.77, 95% CI 1.14-2.77, p = 0.013]. The odds of NSSI increased by 24% for every 10% increase in the percentage of participants with histories of suicide attempts (OR 1.24, 95% CI 1.04-1.48, p = 0.020) and decreased by 26% for every 10% increase in the percentage of participants with histories of substance abuse (OR 0.74, 95% CI 0.58-0.95, p = 0.023).Conclusions. In the specific context of ED, NSSI is highly prevalent and correlates positively with attempted suicide, urging for NSSI-focused treatments. A novel finding is that NSSI is potentially antagonized by substance abuse.

BackgroundImpairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses.Methods104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis.ResultsDuring the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls.ConclusionsIn summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.