Systems genetics of alcoholism

Alcoholism is a common disease resulting from the complex interaction of genetic, social, and environmental factors. Interest in the high heritability of alcoholism has resulted in many studies of how single genes, as well as an individual's entire genetic content (i.e, genome) and the proteins expressed by the genome, influence alcoholism risk. The use of large-scale methods to identify and characterize genetic material (i.e, high-throughput technologies) for data gathering and analysis recently has made it possible to investigate the complexity of the genetic architecture of susceptibility to common diseases such as alcoholism on a systems level. Systems genetics is the study of all genetic variations, their interactions with each other (i.e., epistasis), their interactions with the environment (i.e., plastic reaction norms), their relationship with interindividual variation in traits that are influenced by many genes and contribute to disease susceptibility (i.e, intermediate quantitative traits or endophenotypes (1)) defined at different levels of hierarchical biochemical and physiological systems, and their relationship with health and disease. The goal of systems genetics is to provide an understanding of the complex relationship between the genome and disease by investigating intermediate biological processes. After investigating main effects, the first step in a systems genetics approach, as described here, is to search for gene gene (i.e, epistatic) reactions. KEY WORDS: Alcoholism; alcoholism etiology; genomics; genetics; systems genetics; epistasis; gene gene interactions; genome-wide studies; biological epistasis; statistical epistasis; risk factors; protective factors; disease etiology; literature review.

Alcohol addiction is a complex disease that results from a variety of genetic, social, and environmental influences. Alcoholism affected approximately 4.65 percent of the U.S. population in 2001-2002, producing severe economic, social, and medical ramifications (Grant 2004). Researchers estimate that between 50 and 60 percent of alcoholism risk is determined by genetics (Goldman and Bergen 1998; McGue 1999). This strong genetic component has sparked numerous linkage and association studies investigating the roles of chromosomal regions and genetic variants in determining alcoholism susceptibility. To date, some of these studies have identified potential susceptibility genes. However, the complex etiology of alcoholism lends itself to further investigation that takes into account the multiple layers of interaction between genes within the context of both the genome and environment.

Systems genetics offers a new approach to studying the progression of multifaceted diseases such as alcoholism. This new and emerging field is the result of the synergy of disciplines such as bioinformatics, biotechnology, epidemiology, genetics, molecular biology, physiology, psychology, and statistics, all of which contribute to a more complete understanding of the interactions and functions of the entire genome with given ecological and sociological contexts. Detecting, characterizing, and interpreting gene-gene and gene-environment interactions as risk factors for alcoholism is an important first step in a systems genetics approach that combines genomimics (2) and proteomics (3) data with methods to understand how biological processes work together to determine human health. This approach does not, however, negate the need to look for variants that directly impact disease independent of interaction effects (main effects) within the data.

A complete review of all results from genetic, genomic, proteomic, and metabolic studies of alcoholism is beyond the scope of this review. This article focuses on recent literature involving studies of genes selected based on biochemical evidence for their role in disease (i.e., candidate genes) and genome-wide studies, followed by an overview of the interaction among genes (i.e., epistasis) and its current and potential application in the study of alcoholism. This article concludes with a discussion of several methods currently being developed that incorporate a systems approach to genetics and their potential applications for the future study of alcoholism.

ALCOHOLISM GENETICS: A BRIEF OVERVIEW

The genetic architecture of susceptibility to a disease such as alcoholism can be defined as (1) the number of genes directly or indirectly involved, (2) the interindividual variation in those genes, and (3) the magnitude and nature of their specific genetic effects. Alcoholism develops in susceptible individuals as a result of genetic, environmental (e.g., alcohol consumption), and social influences, as well as their propensity for risk-taking behaviors (Ramoz et al. 2006). Because of this complex etiology, multiple levels of information must be integrated to more completely understand the genetic architecture of alcoholism. In the progression of multifactorial diseases such as alcoholism, gene-gene interactions result in a variety of differentially expressed proteins. These proteins also interact, resulting in certain biochemical and physiological characteristics that, in the presence of certain environmental influences, result in alcoholism. Although studies of alcoholism's etiology have been successful in identifying a few candidate genes for susceptibility, interindividual variation in these genes accounts for only a small proportion of the overall heritability of the disease. Much of the remaining heritability is potentially due to DNA sequence variations, with effects that are dependent on contexts defined by the rest of the genome and the environment.