SMAD4 and chronic obstructive pulmonary disease: Among the listed biological pathways linked to the mapped genes (Table 4), several pathways play a significant role in lung function and/or COPD, including downregulation of SMAD2/3: SMAD4 transcriptional activity, circadian entrainment, GABA B receptor activation, and activation of G protein-gated potassium channels [25, 29–32].