Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association (GWA) meta-analysis based in 135,458 cases and 344,901 control, We identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression, and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relations of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk. Molecular Psychiatry (2004) 9, 908-915.

Anxiety disorders constitute the largest group of mental disorders in most western societies and are a leading cause of disability. The essential features of anxiety disorders are excessive and enduring fear, anxiety or avoidance of perceived threats, and can also include panic attacks. Although the neurobiology of individual anxiety disorders is largely unknown, some generalizations have been identified for most disorders, such as alterations in the limbic system, dysfunction of the hypothalamic-pituitary-adrenal axis and genetic factors. In addition, general risk factors for anxiety disorders include female sex and a family history of anxiety, although disorder-specific risk factors have also been identified. The diagnostic criteria for anxiety disorders varies for the individual disorders, but are generally similar across the two most common classification systems: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases, Tenth Edition (ICD-10). Despite their public health significance, the vast majority of anxiety disorders remain undetected and untreated by health care systems, even in economically advanced countries. If untreated, these disorders are usually chronic with waxing and waning symptoms. Impairments associated with anxiety disorders range from limitations in role functioning to severe disabilities, such as the patient being unable to leave their home.

The objective of this study was to examine the associations between persistent childhood sleep problems and adulthood anxiety and depression. Parents of 943 children (52% male) participating in the Dunedin Multidisciplinary Health and Development Study provided information on their children's sleep and internalizing problems at ages 5, 7, and 9 years. When the participants were 21 and 26 years, adult anxiety and depression were diagnosed using a standardized diagnostic interview. After controlling for childhood internalizing problems, sex, and socioeconomic status, persistent sleep problems in childhood predicted adulthood anxiety disorders (OR (95% CI) = 1.60 (1.05-2.45), p = .030) but not depressive disorders (OR (95% CI) = .99 (.63-1.56), p = .959). Persistent sleep problems in childhood may be an early risk indicator of anxiety in adulthood.

These data provide evidence for phenotypic and genetic overlap as well as differentiation between aspects of anxiety-related behaviours in young children. We conclude that research with young children will benefit from more specific assessments of anxiety-related behaviours in addition to less differentiated assessments of 'internalising' symptoms.

Objective Irritability has been proposed to underlie the developmental link between oppositional problems and depression. However, little is known about the genetic and environmental influences on irritability and its overlap with depression. This paper tests the hypothesis that the association between irritability and depression is accounted for by genetic factors. As such, it draws on the notion of “generalist genes” i.e., genes of general effect that underlie phenotypic overlap between disorders. Method The G1219 study, a UK-based twin sample (N=2651), was used in a cross-sectional and longitudinal design. Irritable and headstrong/hurtful dimensions of oppositional behavior were derived using factor analysis. Regression was used to estimate the association between depression and delinquency. Multivariate genetic analyses were used to estimate the genetic overlap between irritability versus headstrong/hurtful behaviors with depression and delinquency respectively. Results Irritability showed a significantly stronger phenotypic relationship with depression than delinquency, whereas headstrong/hurtful behaviors were more strongly related to delinquency than depression. In multivariate genetic analyses, the genetic correlation between irritability and depression (0.70; CI: 0.59-0.82) was significantly higher than that between irritability and delinquency (0.57; CI: 0.45-0.69); conversely, the genetic correlation between headstrong/hurtful behaviors and delinquency (0.80; CI: 0.72-0.86) was significantly higher than that between headstrong/hurtful behaviors and depression (0.46; CI: 0.36-0.57). In longitudinal models, the phenotypic association between irritability at Time 1 and depression at Time 2 was accounted for by the genetic association between irritability and depression at Time1. Conclusions The findings are consistent with the theory that genes with general effects underlie the relationship between irritability and depression.

Anxiety disorders are one of the most common, debilitating and costly classes of psychiatric disorders worldwide. Twin studies estimate heritability of anxiety disorders to be between 30%-60%, depending on specific disorder, age, and level of impairment. Although individual anxiety disorders are considered clinically distinct, they share much of their phenotypic and genetic variance, potentially reflecting an underlying liability distribution. The UK Biobank has collected symptom and disorder level anxiety data on 157,366 individuals across the UK who have contributed their genetic data. We used this dataset to investigate genome-wide associations, SNP based heritability, and genetic correlations in four anxiety phenotypes. These reflect population level current anxiety symptoms as a quantitative phenotype, and three case control phenotypes; severe current anxiety symptoms, probable lifetime generalised anxiety disorder and self-reported lifetime diagnosis of any anxiety disorder. Probable lifetime generalised anxiety disorder and selfreported lifetime diagnosis of any anxiety disorder were meta-analysed with a comparable genome-wide association study of anxiety. Genetic analyses included unrelated Caucasian individuals of Western European ancestry. Estimates of SNP heritability from common variants ranged between 4% (for population level anxiety symptoms) and 32% (for probable generalised anxiety disorder), and all four UK Biobank anxiety phenotypes are highly genetically correlated. Three genome-wide significant loci were found to be associated with anxiety. Both rs3807866 located in the TMEM106B protein coding region on chromosome 7, and rs2996471 located in the NTRK2 protein coding region on chromosome 9, were associated with self-report of any lifetime anxiety diagnosis. An additional non characterised region on chromosome 9 was associated with both self report of any lifetime anxiety diagnosis (rs10809485), and severe anxiety symptoms (rs17189482). Meta-analysis with a comparable genome-wide association study of anxiety did not result in additional findings. This represents the largest genetic study of anxiety to date-however larger sample sizes will be required to further examine the common genetic architecture underlying anxiety. .