Among the 19 causal genes identified by the discovery PWAS of depression, some play a role at the synapse. These include synaptogenesis (B3GALTL)35,36, synaptic signaling (CTNND1)37,38, and synaptic plasticity (EPHB2 and P2RX7)39,40. Specifically, B3GALTL, also known as B3GLCT, is a glycosyltransferase that adds glycans to proteins in the process of glycosylation, an abundant post-translational modification41. Via glycosylation, B3GALTL stabilizes thrombospondin 1 (TSP-1), a protein that induces synaptogenesis35,36, implicating B3GALTL in synaptogenesis. Our depression PWAS findings suggest that participants with depression had lower abundance of B3GALTL protein in the brain, which may negatively affect the stability of TSP-1 and subsequently synaptogenesis. Consistent with our finding, TSP-1 was upregulated in rat hippocampi following treatment of depression using electroconvulsive therapy, which quickly and effectively reverses the symptoms of depression in the short-term42. Taken together, decreased B3GALTL protein may negatively affect synaptogenesis, which may contribute to the pathogenesis of depression. Regarding synaptic signaling, CTNND1 functions in the glutamatergic excitatory synaptic signaling pathway during neuronal development38. With regard to synaptic plasticity, EPHB2 is an essential component of hippocampal synaptic plasticity39, and a number of studies
