Coordinate expression of genes form highly organized biological networks within specific regions of human brain, that are reproducible across individuals 12, 13. The homeostatic structure of molecular networks may be disrupted through genetic and environmental perturbations producing long-lasting interactions involved in complex traits 14. Integrating multiple components and layers of information within the framework of a biological network helps identify and prioritize individual transcripts, as well as sets of co-regulated transcripts associated with disease 15. Due to the long-standing cellular adaptations caused by substance dependence 16, 17, we hypothesize that alcohol dependence is shaped, at least in part, by persistent differences in coexpression systems collectively affecting the propensity for compulsive alcohol consumption. Through massive parallel sequencing of RNA transcripts from postmortem human prefrontal cortex (PFC), a prominent brain area involved in addiction 18, 19, our bioinformatics approach used transcriptional networks and genetic variation in conjunction with estimates of lifetime alcohol consumption to determine groups of coexpressed molecular elements associated with alcohol dependence. Our analysis provides convergent systems-level evidence of genetic networks within PFC that contribute to the pathophysiology of alcohol drinking behavior in humans.
