PROJECT SUMMARY This project addresses the need for a better understanding of the causes of major depressive disorder (MDD) as a way to improve diagnosis and treatment for the world's leading cause of disability. Genetic approaches, a path to identifying causal factors and hence finding novel treatments, are proving successful in some psychiatric disorders, but their application in MDD poses challenges, due to the condition's heterogeneity and the importance of environmental factors. Success requires studies that take into account heterogeneity by assessing multiple clinical features, and include measures of environmental risk factors. Furthermore, genetic studies need to expand their reach to include multiple, ethnically diverse populations, so as to identify additional risk loci, enable fine-mapping and the identification of likely causal variants, and expand the use of polygenic predictors of disease to more populations. NIMH, in issuing PAR-20-026, “Genetic Architecture of Mental Disorders in Ancestrally Diverse Populations”, recognizes this need and in response to this call, we have established an international collaboration of investigators from South Korea and the United States, with a strong track record of large-scale psychiatric genetic research in East Asia. We will create the largest East Asian cohort available for the discovery of new MDD genes, increase the diversity of genetic discovery efforts (a step towards reducing health disparities), and perform exhaustive analyses to identify likely causal variants and genes involved in MDD. The aims of the consortium are as follows: Aim 1: To collect from South Korea DNA samples and phenotypes from 10,000 women with severe recurrent MDD and from 10,000 matched, screened, controls. We will obtain a comprehensive set of clinical features and risk factors, a deep set of phenotypes that provide a powerful resource for gene identification. Aim 2: We will genotype samples, map risk loci for MDD in the Korean sample, identify sources of heterogeneity and examine how genes and environment interact to cause MDD. Aim 3: Identify genetic loci specific for MDD in a meta-analysis of East Asian cohorts, and refine likely sets of causal variants by using trans-ancestry fine-mapping in cohorts of different ethnicities.