Identification of 64 new risk loci for major depression, refinement of the genetic architecture and risk prediction of recurrence and comorbidities

Abstract

Major depression (MD) is a common mental disorder and a leading cause of disability worldwide. We conducted a GWAS meta-analysis of more than 1.3 million individuals, including 371,184 with MD, identifying 243 risk loci. Sixty-four loci are novel, including glutamate and GABA receptors that are targets for antidepressant drugs. Several biological pathways and components were enriched for genetic MD risk, implicating neuronal development and function. Intersection with functional genomics data prioritized likely causal genes and revealed novel enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found MD to be highly polygenic, with around 11,700 variants explaining 90% of the SNP heritability. Bivariate Gaussian mixture modeling estimated that > 97% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and ADHD) are influencing MD risk when both concordant and discordant variants are considered, and nearly all MD risk variants influence educational attainment. Additionally, we demonstrated that MD genetic risk is associated with impaired complex cognition, including verbal reasoning, attention, abstraction and mental flexibility. Analyzing Danish nation-wide longitudinal data, we dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across case subgroups of MD recurrency and psychiatric comorbidity and demonstrating two-to six-fold increases in absolute risks for developing comorbid psychiatric disorders among MD cases with the highest versus the lowest polygenic burden. The results deepen the understanding of the biology underlying MD and its progression and inform precision medicine approaches in MD.