Major depressive disorder is among the leading causes of disease burden and disability, as well as a major public health concern worldwide. Despite its substantial heritability, no robustly replicated genetic risk loci had been found until recently. Now, a new study has identified, and replicated, two variants associated with an increased risk for this disorder. The success of this study appears to lie in the use of low-coverage sequencing, instead of microarrays, and in minimizing phenotypic and genetic heterogeneity.