Broad definition of depression (BroadDep) had high genetic correlation with recurrent MDD (RecurMDD), but relative low correlation with MDD defined by electroconvulsive therapy (ECTMDD).

Different definitions of depression showed substantially different genetic correlation and causality with other psychiatric traits.

BroadDep and RecurMDD shared large amounts of genetic loci, but no locus was jointly associated with RecurMDD and ECTMDD.

Depression is a common and complex psychiatric illness with considerable heritability. Genome-wide association studies (GWAS) have been conducted among different definitions of depression based on different diagnostic criteria. However, the heritability explained by different depression GWAS and the identified loci varied widely. To understand the genetic architectures of different definitions of depression, we conducted a series of genetic analyses including linkage disequilibrium score regression (LDSC), Mendelian randomization, and polygenic overlap quantification and identification. Different definitions of depression and other common psychiatric traits were included in this analysis. We found that although genetic correlations between different definitions of depression were relatively high, they showed substantially different genetic correlation and causality with other psychiatric traits. Using bivariate causal mixture mode (MiXeR) and conjunctional false discovery rate (conjFDR) approach, we observed both shared and unique risk loci across different definitions of depression. Further functional mapping with expression quantitative trait loci (eQTL) information from multiple brain tissues and single cell types indicated distinct genes underlying different definitions of depression, and pathways associated with synapses were significantly enriched in the illness. Our study showed that the genetic architectures of different definitions of depression were distinct and genetic studies of depression should be conducted more cautious.

Depression

GWAS

Genetic correlation

Mendelian randomization

Polygenic overlap

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