43 - GENOME-WIDE ASSOCIATION ANALYSES IDENTIFY 44 RISK VARIANTS AND REFINE THE GENETIC ARCHITECTURE OF MAJOR DEPRESSIVE DISORDER

Abstract

Background Major Depressive Disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. MDD is a major cause of disability worldwide. Twin studies attribute ~40% of the variation in liability to MDD to additive genetic effects, and may be greater for recurrent, early-onset, and postpartum MDD. GWA studies of MDD have had notable difficulties in identifying loci. Previous findings suggest that an appropriately designed study should identify susceptibility loci. Methods We conducted a Genome-Wide Association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls. We used the standard GWA mega/meta-analysis methods of the core PGC quality control, imputation, and analysis pipeline (i.e., ricopili) Results We identified 44 independent loci that met criteria for statistical significance. We can make a strong case for the identification of RBFOX1 and NEGR1. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences in MDD cases vs controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5e-10), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. Discussion We present extensive analyses of these results which provide new insights into the nature of MDD. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.