Here, we present a large GWAS meta-analysis of depression which included expanded iPSYCH26 and FinnGen23 cohorts, as well as PGC, UKB, 23andMe and MVP data25, revealing numerous novel risk loci and infer pathophysiologic implications of associated variants by intersecting with functional genomics data. We refine the genetic architecture of depression and case subgroups and demonstrate the impact of depression genetic risk on domains of cognitive performance. Leveraging nation-wide longitudinal health data on the Danish iPSYCH cohort, we dissect the genetic architecture of single-episode and recurrent depression as well as individuals who have developed anxiety, bipolar disorder, schizophrenia and SUD comorbidities. Furthermore, to inform precision psychiatry approaches, we calculate time-dependent absolute risks and hazard rate ratios for developing recurrent depression, anxiety, bipolar disorder, schizophrenia and SUD depending on different polygenic burdens of depression
