A global overview of shared genetic architecture between smoking behaviors and major depressive disorder in European and East Asian ancestry.

Background: The co-occurrence of smoking behaviors and major depressive disorder (MDD) has been widely documented in populations. However, the underlying mechanism of this association remains unclear.

Methods: Genome-wide association studies of smoking behaviors and MDD, combined with multi-omics datasets, were usedto characterise genetic correlations, identify shared loci and genes, and explore underlying biological mechanisms. Mendelian randomization (MR) analyses were conducted to infer causal relationships between smoking behaviors and MDD. Druggability analyses were performed to identify potential drugs with both antidepressant and smoking cessation effects.

Results: Extensive overall genetic correlations were found between smoking behaviors and MDD. Furthermore, eighteen local regions showed significant genetic correlations, which could be partly explained by gene co-expression patterns. We identified 24 shared loci and 120 genes, which were enriched in limbic system, GABAergic and dopaminergic neurons, as well as in synaptic pathways. Through integrating with tissue specific information, seven key genes (ANKK1, NEGR1, USP4, TCTA, SORCS5, SPPL3, and USP28) were pinpointed. Notably, druggability analyses supported ANKK1 as a potential drug target for the treatment of MDD and tobacco dependence. MR analyses suggested a bidirectional causal relationship between smoking initiation and MDD. Although findings in East Asian ancestry were limited, the shared locus (chr15:47613403-47,685,504) identified in European ancestry remained significant in East Asian ancestry.

Conclusions: Our findings suggest the extensive genetic overlap between smoking behaviors and MDD, support the role of limbic system and synapse involved in shared mechanisms, and implicate for prevention, intervention and treatment.