Given that alcohol use disorder (AUD) and major depressive disorder (MDD) are frequently comorbid in humans (Yoon et al., 2015), and that AUD can prospectively predict future MDD (Boschloo et al., 2012; Brière et al., 2014), a speculative mechanistic explanation is that chronic alcohol use leads to downregulation of HCN2 in VTA dopamine neurons, which may directly contribute to the development of depressive behavior. The gene discussed is HCN2; the disease is major depressive disorder.