Objective: Suicide death is a highly preventable, yet growing, worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizeable suicide death cohorts available for study. To address this limitation, we conducted the first comprehensive genomic analysis of suicide death, using a previously unpublished suicide cohort. Methods:The analysis sample consisted of 3,413 population-ascertained cases of European ancestry and 14,810 ancestrally matched controls. Analytical methods included principle components analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic relatedness matrix), gene and gene set enrichment testing, polygenic score analyses, as well as SNP heritability and genetic correlation estimation using LD score regression.Results: GWAS identified two genome-wide significant loci (6 SNPs, p<5x10 -8 ). Gene-based analyses implicated 19 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide heritability was estimated h 2 =0.2463, SE = 0.0356 using summary statistics from a multivariate logistic GWAS adjusting for ancestry. Notably, suicide polygenic scores were robustly predictive of out of sample suicide death, as were polygenic scores for several other psychiatric disorders and psychological traits, particularly behavioral disinhibition and major depressive disorder. Conclusions:In this report, we identify multiple genome-wide significant loci/genes, and demonstrate robust polygenic score prediction of suicide death case-control status, adjusting for ancestry, in independent training and test sets. Additionally, we report that suicide death cases have increased genetic risk for behavioral disinhibition, major depression, autism spectrum disorder, psychosis, and alcohol use disorder relative to controls. Results demonstrate the ability of polygenic scores to robustly, and multidimensionally, predict suicide death case-control status..

Background The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti‐PD‐1 (aPD‐1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front‐line BRAF/MEKi, aPD‐1, or niv/ipi. Methods Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD‐1 in the front‐line setting were identified from a nationwide database comprising de‐identified patient‐level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan‐Meier curves and log‐rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front‐line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival. Results Five hundred and sixty seven patients with advanced disease and treated with front‐line aPD‐1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow‐up of 22.4 months, median overall survival (OS) for patients treated with front‐line niv/ipi was not reached (NR) while median OS for patients treated with aPD‐1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front‐line treatment with PD‐1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses. Conclusions In our real‐world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front‐line niv/ipi or aPD‐1 had longer survival compared to those treated with front‐line BRAF/MEKi.