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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

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Youths with BP spectrum disorders showed a continuum of BP symptom severity from subsyndromal to full syndromal with frequent mood fluctuations. Results of this study provide preliminary validation for BP-NOS.

Children and adolescents with BP-II and BP-NOS have a phenotype that is on a continuum with that of youth with BP-I. Elevated mood is a common feature of youth with BP-spectrum illness.

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.

Objective-To assess the longitudinal course of youth with bipolar spectrum disorders.Methods-413 youth (7-17 years) with bipolar-I (n=244), bipolar-II (n=28), and bipolar NotOtherwise-Specified (NOS) (n=141) were recruited mainly from outpatient clinics at the University of Pittsburgh, Brown, and UCLA. Symptoms were ascertained retrospectively on average every 9.4 months for 4 years using the Longitudinal Interval Follow-up Evaluation. Rates and time to recovery and recurrence and week-by-week symptomatic status were analyzed.Results-Approximately 2.5 years after onset of their index episode, 81.5% of subjects fully recovered, but 1.5 years later 62.5% had a syndromal recurrence, particularly depression. One-third of the subjects had one syndromal recurrence and 30% ≥ 2 syndromal recurrences. The polarity of the index episode predicted the polarity of subsequent episodes. Subjects were symptomatic during 60% of follow-up time, particularly with subsyndromal symptoms of depression and mixed-polarity, with numerous changes in mood polarity. Manic symptomatology, especially syndromal, was less frequent and bipolar-II was mainly manifested by depressive symptoms. Forty-percent of subjects had syndromal and/or subsyndromal symptoms during 75% of follow-up period. During 17% of follow-up time subjects, especially those with bipolar-I, experienced psychosis. Twenty-five percent of bipolar-II subjects converted into bipolar-I and 38% of bipolar-NOS converted into bipolar -I/II. Early-onset, bipolar-NOS, long duration, low socio-economic status, and family history of mood disorders were associated with poorer outcomes.Conclusions-Bipolar spectrum disorder in youth is an episodic disorder characterized by subsyndromal and, less frequently, syndromal episodes with mainly depressive and mixed symptoms and rapid mood changes.

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