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Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

Objective To conduct a genome-wide association study (GWAS) of anorexia nervosa and to calculate genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method Following uniform quality control and imputation using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, we performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression (LDSC) was used to calculate genome-wide common variant heritability [ hSNP2, partitioned heritability, and genetic correlations (rg)] between anorexia nervosa and other phenotypes. Results Results were obtained for 10,641,224 single nucleotide polymorphisms (SNPs) and insertion-deletion variants with minor allele frequency > 1% and imputation quality scores > 0.6. The hSNP2 of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. We identified one genome-wide significant locus on chromosome 12 (rs4622308, p=4.3×10−9) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high density lipoprotein (HDL) cholesterol, and significant negative genetic correlations between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions Anorexia nervosa is a complex heritable phenotype for which we have found the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. Our results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Complex posttraumatic stress disorder (CPTSD) has been proposed as a diagnosis for capturing the diverse clusters of symptoms observed in survivors of prolonged trauma that are outside the current definition of PTSD. Introducing a new diagnosis requires a high standard of evidence, including a clear definition of the disorder, reliable and valid assessment measures, support for convergent and discriminant validity, and incremental validity with respect to implications for treatment planning and outcome. In this article, the extant literature on CPTSD is reviewed within the framework of construct validity to evaluate the proposed diagnosis on these criteria. Although the efforts in support of CPTSD have brought much needed attention to limitations in the trauma literature, we conclude that available evidence does not support a new diagnostic category at this time. Some directions for future research are suggested.

Posttraumatic stress disorder (PTSD) is a debilitating condition that affects approximately 10% of women in the United States. Although effective psychotherapeutic treatments for PTSD exist, clients with PTSD report additional benefits of complementary and alternative approaches such as yoga. In particular, yoga may downregulate the stress response and positively impact PTSD and comorbid depression and anxiety symptoms. We conducted a pilot study of a randomized controlled trial comparing a 12-session Kripalu-based yoga intervention with an assessment control group. Participants included 38 women with current full or subthreshold PTSD symptoms. During the intervention, yoga participants showed decreases in reexperiencing and hyperarousal symptoms. The assessment control group, however, showed decreases in reexperiencing and anxiety symptoms as well, which may be a result of the positive effect of self-monitoring on PTSD and associated symptoms. Between-groups effect sizes were small to moderate (0.08-0.31). Although more research is needed, yoga may be an effective adjunctive treatment for PTSD. Participants responded positively to the intervention, suggesting that it was tolerable for this sample. Findings underscore the need for future research investigating mechanisms by which yoga may impact mental health symptoms, gender comparisons, and the long-term effects of yoga practice.

Objective The comorbidity of posttraumatic stress disorder (PTSD) and eating disorders (EDs) is high among women but has been understudied in men. Little is known about the association between partial or subthreshold PTSD and EDs among women or men. Method This study included PTSD and ED data from male (n=2382) and female (n=3310) National Comorbidity Survey-Replication study participants. Results The vast majority of women and men with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) reported a history of interpersonal trauma. Rates of PTSD were significantly higher among women and men with BN and BED. Subthreshold PTSD was more prevalent than threshold PTSD among women with BN and women and men with BED. Discussion Interpersonal forms of trauma, PTSD, and subthreshold/partial PTSD, were prevalent among men and women with EDs. Findings highlight the importance of assessing for trauma and PTSD in ED patients.

Background Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. Methods We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci (QTL) associated with binge eating. We used gene targeting to validated candidate genetic factors. Finally, we used transcriptome analysis of the striatum via mRNA sequencing (RNA-seq) to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. Results C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant QTL on chromosome 11 (LOD=7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms “morphine addiction” and “retrograde endocannabinoid signaling” whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. Conclusions We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

Recent proposals for revisions to the 11th edition of the International Classification of Diseases (ICD-11) posttraumatic stress disorder (PTSD) diagnostic criteria have argued that the current symptom constellation under the Diagnostic and Statistical Manual of Mental Disorders-5 is unwieldy and includes many symptoms that overlap with other disorders. The newly proposed criteria for the ICD-11 include only six symptoms. However, restricting the symptoms to those included in the ICD-11 has implications for PTSD diagnosis prevalence estimates, and it remains unclear whether these six symptoms are most strongly associated with a diagnosis of PTSD. Network analytic methods, which assume that psychiatric disorders are networks of interrelated symptoms, provide information regarding which symptoms are most central to a network. We estimated network models of PTSD in a national sample of veterans of the Iraq and Afghanistan wars. In the full sample, the most central symptoms were persistent negative emotional state, efforts to avoid external reminders, efforts to avoid thoughts or memories, inability to experience positive emotions, distressing dreams, and intrusive distressing thoughts or memories; i.e., three of the six most central items to the network would be eliminated from the diagnosis under the current proposal for ICD-11. An empirically-defined index summarizing the most central symptoms in the network performed comparably to an index reflecting the proposed ICD-11 PTSD criteria at identifying individuals with an independently-assessed DSM-5 defined PTSD diagnosis. Our results highlight the symptoms most central to PTSD in this sample, which may inform future diagnostic systems and treatment.