Association Studies) over individual pathway or gene-set enrichment approaches because it conceptualizes and explores vulnerability to AD as a function of the joint and multiplicative distribution of gene, epigene, and proteomic effects that constitute evolutionarily robust biological systems disrupted by alcohol and other drugs. Such models [which include biological (e.g., genetic/transcriptomic variants) and environmental (e.g., presence/absence of alcohol cues or alcohol using relatives/peers) variables] describe how any one perturbation in one aspect of the system (e.g., “Motivation” in Figure 1) affects other components of the system and the manifestation of the disease/trait. Given the lack of large NGS databases, a starting point for Systems Genetics would be the application of sophisticated network-based models to existing GWAS data in order to identify/confirm candidate systems (i.e., network of variation across different biological pathways) that are likely to be more stable and reproducible across independent samples. Notably, the lack of comparable environmental assessments/arrays across studies will make it difficult to replicate environmental effects. In addition to GWAS data network-based models can be made to incorporate micro-array/RNA-Seq (i.e., whole genome sequencing of mRNA transcripts) and Chip-Seq (i.e., whole genome sequencing of immune-precipitation-enriched genomic DNA) data. For instance, although microarray studies have suffered from multiple
