Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction. Genetic correlations among eight neuropsychiatric disorders indicate three genetic factors.After standardized and uniform quality control, additive logistic regression analyses were performed on individual disorders (Methods). A total of 6,786,994 SNPs were common across all datasets and were retained for further study. Using the summary statistics of these SNPs, we first estimated pairwise genetic correlations among the eight disorders using linkage disequilibrium (LD) score regression analyses (Bulik-Sullivan et al., 2015a) (Methods; Fig. 1a; Supplementary Table 2). The results were broadly concordant with previous estimates (Brainstorm Consortium, 2018; Cross-Disorder Group of the Psychiatric Genomics Consoritum, 2013). The genetic correlation was highest between SCZ and BIP (rg = 0.70 ±0.02), followed by OCD and AN (rg = 0.50 ±0.12). Interestingly, based on genome-wide genetic correlations, MD was closely correlated with ASD (rg=0.45 ±0.04) and ADHD (rg=0.44 ±0.03), two childhood-onset disorders. Despite variation in magnitude, significant genetic correlations were apparent for most pairs of disorders, suggesting a complex, higher-order genetic structure underlying psychopathology ( Fig. 1b).We modeled the genome-wide joint architecture of the eight neuropsychiatric disorders using an exploratory factor analysis (EFA) (Gorsuch, 1988), followed by genomic structural equation modeling (SEM) (Grotzinger et al., 2018) (Methods). EFA identified three correlated factors, which together explained 51% of the genetic variation in the eight neuropsychiatric disorders ( Supplementary Table 3). The first factor consisted primarily of disorders characterized by compulsive behaviors, specifically AN, OCD, and, more weakly, TS. The second factor was characterized by mood and psychotic disorders (MD, BIP, and SCZ), and the third factor by three early-onset neurodeve...

Age of onset contains information on the timing of events relevant to disease etiology, but there has not been a systematic investigation of its heritability from GWAS data. Here, we characterize the genetic architecture of age of first occurrence and its genomic relationship with disease susceptibility for a wide range of complex disorders in the UK Biobank. For diseases with a sufficient sample size, we discover that age of first occurrence has non-trivial genetic contributions, some with specific genetic risk factors not associated with susceptibility to the disease. Through genetic correlation analysis, we show that an earlier health-event occurrence is correlated with a higher polygenic risk of disease susceptibility. An independent genetic investigation of the FinnGen cohort replicates the pattern of heritability and genetic correlation estimates. We then demonstrate that incorporating disease onset age with susceptibility may improve genetic risk prediction and stratification.