Genome-wide study of half a million individuals with major depression identifies 697 independent associations, infers causal neuronal subtypes and biological targets for novel pharmacotherapies.

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In a genome-wide association study (GWAS) of 685,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries and across diverse and admixed ancestries, we identify 697 independent associations at 636 genetic loci, 293 of which are novel. Using fine-mapping and functional genomic datasets, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. Leveraging new single-cell gene expression data, we conducted a causal neural cell type enrichment analysis that implicated excitatory and inhibitory midbrain and forebrain neurons, peptidergic neurons, and medium spiny neurons in MD. Critically, our findings are enriched for the targets of antidepressants and provide potential antidepressant repurposing opportunities (e.g., pregabalin and modafinil). Polygenic scores (PGS) from European ancestries explained up to 5.7% of the variance in liability to MD in European samples and PGS trained using either European or multi-ancestry data significantly predicted case control status across all four diverse ancestries. These findings represent a major advance in our understanding of MD across global populations. We provide evidence that MD GWAS reveals known and novel biological targets that may be used to target and develop pharmacotherapies addressing the considerable unmet need for effective treatment.