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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

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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.

Context Mindfulness Based Cognitive Therapy (MBCT) is a group-based psychosocial intervention designed to enhance self-management of prodromal symptoms associated with depressive relapse. Objective To compare rates of relapse in remitted depressed patients receiving MBCT against maintenance antidepressant pharmacotherapy, the current standard of care Design Patients who met remission criteria following 8 months of algorithm informed antidepressant treatment were randomized to either: Maintenance Antidepressant Medication (M-ADM), MBCT or placebo (PLA) and were followed for 18 months. Setting Outpatient clinics at the Centre for Addiction and Mental Health, Toronto and St. Joseph’s Healthcare, Hamilton. Participants One hundred sixty patients aged 18 to 65 meeting DSM-IV for major depressive disorder with a minimum of 2 past episodes. Of these, 84 achieved remission (52.5%) and were assigned to one of the 3 study conditions. Interventions Remitted patients either discontinued their antidepressants and attended eight weekly group sessions of MBCT, continued on their therapeutic dose of antidepressant medication or discontinued active medication onto placebo. Main Outcome Measure Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression on Module A of the SCID. Results Intention to treat analyses revealed a significant interaction between the quality of acute phase remission and subsequent prevention of relapse in randomized patients (p = .03). Among unstable remitters (defined as 1 or more HRSD >7 during remission) patients in both MBCT and M-ADM showed a 73% decrease in hazard compared to PLA (p = .03), whereas for stable remitters (all HRSD ≤ 7 during remission) there were no group differences in survival. Findings remained significant after accounting for the effects of past depressive episodes on relapse. Conclusion For depressed patients who are unwilling or unable to tolerate long term maintenance antidepressant treatment, MBCT offers equivalent protection from relapse.

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Obesity research suffers from an overinclusion paradigm whereby all participants with a BMI beyond a certain cutoff value (e.g., 30) are typically combined in a single group and compared to those of normal weight. There has been little attempt to identify meaningful subgroups defined by their salient biobehavioral differences. In order to address this limitation, we examined genetic and psychological indicators of hedonic eating in obese adults with (n = 66) and without (n = 70) binge eating disorder (BED). Our analyses focused on dopamine (DA) and opioid genetic markers because of their conjoint association with the functioning of brain reward mechanisms. We targeted three functional polymorphisms related to the D2 receptor (DRD2) gene, as well as the functional A118G polymorphism of the mu‐opioid receptor (OPRM1) gene. We found that significantly more obese controls had the “loss‐of‐function” A1 allele of Taq1A compared to their BED counterparts, whereas the “gain‐of‐function” G allele of A118G occurred with greater frequency in the BED group. A significant gene–gene combination χ2 analysis also indicated that of those participants with the gain‐gain genotype (G+ and A1), 80% were in the BED group whereas only 35% with the loss‐loss genotype (G− and A1+) were in this group. Finally, BED subjects had significantly higher scores on a self‐report measure of hedonic eating. Our findings suggest that BED is a biologically based subtype of obesity and that the proneness to binge eating may be influenced by a hyper‐reactivity to the hedonic properties of food—a predisposition that is easily exploited in our current environment with its highly visible and easily accessible surfeit of sweet and fatty foods.

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