Alcohol’s genetic complexity highlights the need for comprehensive models that account for the cumulative, pleiotropic, and epistatic effects of genes in the context of the rest of the genome and the environment. System-based genetic studies (i.e., Systems Genetics) of AD have become increasingly possible because of the major advances in genomics, proteomics, gene x environment interaction and correlation studies, and epigenetics. Systems-based approaches that conceptualize and model the susceptibility to AD as combinatorial effects of genetic, epigenetic, transcriptomic, and proteomic variation are likely to prove useful in overcoming these challenges. The advantage of a systems-based framework over agnostic testing procedures is that it organizes the distribution of “relatively modestly effective” variants into profiles that might better inform our understanding of specific aspects of the development of alcohol use disorders. We propose Systems Genetics (a combination of Systems Biology and Genetic 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
