A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants.

The exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) and 5,000 controls were analyzed, finding that individuals with ASD and individuals with ADHD had a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly higher than controls. This motivated a combined analysis across ASD and ADHD, identifying microtubule-associated protein 1A (MAP1A) as a new exome-wide significant gene conferring risk for childhood psychiatric disorders.

A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

A comparison of selected risk factors for unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a danish population-based cohort.

OBJECTIVE: Growing evidence of an etiologic overlap between schizophrenia and bipolar disorder has become increasingly difficult to disregard. In this study, we examined paternal age, urbanicity of place of birth, being born "small for gestational age," and parental loss as risk factors for primarily schizophrenia and bipolar disorder, but also unipolar depressive disorder and schizo-affective disorder. Furthermore, we examined the incidence of the disorders in a population-based cohort and evaluated our results in the context of the Kraepelinian dichotomization. METHOD: We established a register-based cohort study of more than 2 million persons born in Denmark between January 1, 1955, and July 1, 1987. Overall follow-up began on January 1, 1973 and ended on June 30, 2005. Relative risks for schizophrenia, bipolar disorder, unipolar depressive disorder, and schizoaffective disorder (ICD-8 or ICD-10) were estimated by survival analysis, using Poisson regression. RESULTS: Differences were found in age-specific incidences. Loss of a parent (especially by suicide) was a risk factor for all 4 disorders. High paternal age and urbanization at birth were risk factors for schizophrenia. Children born pre-term had an excess risk of all disorders except schizophrenia if they were born "small for gestational age." CONCLUSIONS: An overlap in the risk factors examined in this study was found, and the differences between the phenotypes were quantitative rather than qualitative, which suggests a genetic and environmental overlap between the disorders. However, large gender differences and differences in the age-specific incidences in the 4 disorders were present, favoring the Kraepelinian dichotomization.