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.

SYNOPSISMany of the standardized interviews currently used in psychiatry require the interviewer to use expert psychiatric judgements in deciding upon the presence or absence of psychopathology. However, when case definitions are standardized it is customary for clinical judgements to be replaced with rules. The Clinical Interview Schedule was therefore revised, in order to increase standardization, and to make it suitable for use by ‘lay’ interviewers in assessing minor psychiatric disorder in community, general hospital, occupational and primary care research.Two reliability studies of the revised Clinical Interview Schedule (CIS-R) were conducted in primary health care clinics in London and Santiago, Chile. Both studies compared psychiatrically trained interviewer(s) with lay interviewer(s). Estimates of the reliability of the CIS-R compared favourably with the results of studies of other standardized interviews. In addition, the lay interviewers were as reliable as the psychiatrists and did not show any bias in their use of the CIS-R. Confirmatory factor analysis models were also used to estimate the reliabilities of the CIS-R and self-administered questionnaires and indicated that traditional measures of reliability are probably overestimates.

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

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P< 0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5×10−8), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083–53 822 102, minimum P= 5.9×10−9 at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Objective: To determine whether poverty and unemployment increase the likelihood of or delay recovery from common mental disorders, and whether these associations could be explained by subjective financial strain. Design: Prospective cohort study. Setting: England, Wales, and Scotland. Subjects: 7726 adults aged 16-75 living in private households. Main outcome measures: Common mental disorders were assessed using the general health questionnaire, a self assessed measure of psychiatric morbidity. Results: Poverty and unemployment (odds ratio 1.86, 95% confidence interval 1.18 to 2.94) were associated with the maintenance but not onset of episodes of common mental disorders. Associations between poverty and employment and maintenance of common mental disorders, however, were much smaller than those of cross sectional studies. Financial strain at baseline was independently associated with both onset (1.57, 1.19 to 2.07) and maintenance (1.86, 1.36 to 2.53) even after adjusting for objective indices of standard of living. Conclusions: Poverty and unemployment increased the duration of episodes of common mental disorders but not the likelihood of their onset. Financial strain was a better predictor of future psychiatric morbidity than either of these more objective risk factors though the nature of this risk factor and its relation with poverty and unemployment remain unclear.