PMC

Top scoring GeneGo network including TNF and MTHFR. This four-gene network is the best fit found by GeneGo (p-value 3.45e-08) for TNF and MTHFR. TNF (TNF-alpha) activates TNFR (TNF-R1), which then activates NF-kB. NF-kB regulates the expression of both MTHFR and TNF, creating a feedback loop among TNF, TNFR, and NF-kB.

GeneGo graphic illustrating how TNF signaling impacts one-carbon metabolism. Folate metabolism is one element of one-carbon metabolism and TNF signaling influences all of the enzymes involved. As a result, variations in any of the genes involved in one-carbon metabolism could influence folate metabolism and susceptibility to depression.

Analysis Flow. Analysis started with prior evidence of potential genetic and environmental influences on comorbidity, followed by testing for genetic influences, genetic interactions, and environmental influences. The resulting model of gene-by-environment interaction is consistent with clinical and biochemical data.

Proposed Model of Comorbid Depression with AUD. This model, incorporating evidence gathered in hypothesis testing, and consistent with an environmental effect of ethanol on the genetic network, shows how ethanol consumption would be expected to result in decreased folate metabolism and increased susceptibility to depression for genetically susceptible individuals.