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.

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.

Background Child maltreatment is a potent risk factor for psychopathology. Although the developmental timing of first exposure to maltreatment is considered important in shaping risk of future psychopathology, no consensus exists on whether earlier or later exposures are more deleterious. This study examines whether age at first exposure to abuse is associated with subsequent depression and suicidal ideation. Methods Data were drawn from the National Longitudinal Study on Adolescent Health (n=15,701). Timing of first maltreatment exposure was classified using: (1) a crude measure capturing early childhood (0–5), middle childhood (6–10), or adolescence (11–17); and (2) a refined measure capturing infancy (0–2), preschool (3–5), latency (6–8), prepubertal (9–10), pubertal (11–13), or adolescence (14–17). We examined whether timing of first exposure was associated with depression and suicidal ideation in early adulthood in the entire sample and among those exposed to maltreatment. Results Respondents exposed to physical abuse at any age had a higher odds of depression and suicidal ideation in young adulthood than non-maltreated respondents. Among maltreated respondents, exposure during early childhood (0–5), particularly pre-school (3–5), was most strongly associated with depression. Respondents first exposed to physical abuse during preschool had a 77% increase in the odds of depression and those first exposed to sexual abuse during early childhood had a 146% increase in the odds of suicidal ideation compared to respondents maltreated as adolescents. Conclusions Developmental timing of first exposure to maltreatment influences risk for depression and suicidal ideation. Whether these findings are evidence for biologically-based sensitive periods requires further study.