Systems Genetics of Alcoholism Chantel D. Sloan; Vicki Sayarath, M.P.H., R.D.; and Jason H. Moore, Ph.D. 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 endophenotypes1) 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 lcohol addiction is a complex of multifaceted diseases such as alco- and metabolic studies of alcoholism disease that results from a variety holism. This new and emerging field is beyond the scope of this review. A of genetic, social, and environ- is the result of the synergy of disciplines This article focuses on recent literature mental influences. Alcoholism affected such as bioinformatics, biotechnology, involving studies of genes selected approximately 4.65 percent of the U.S. epidemiology, genetics, molecular population in 2001–2002, producing biology, physiology, psychology, and 1 An endophenotype is a genetically determined trait severe economic, social, and medical statistics, all of which contribute to (i.e., phenotype) that is not immediately visible but may contribute to the susceptibility to develop a particular ramifications (Grant 2004). Researchers a more complete understanding of behavior or syndrome. See the glossary, p. 84, for estimate that between 50 and 60 per- the interactions and functions of the descriptions of other technical terms used in this article. cent of alcoholism risk is determined entire genome with given ecological 2 Genomics is the study of the structure and function of by genetics (Goldman and Bergen 1998; and sociological contexts. Detecting, an organism’s complete genetic content, or genome. characterizing, and interpreting gene– McGue 1999). This strong genetic 3 Proteomics is the study of the complete set of proteins component has sparked numerous link- gene and gene–environment interac- produced by an organism (i.e., proteome). age and association studies investigat- tions as risk factors for alcoholism is ing the roles of chromosomal regions an important first step in a systems CHANTEL D. SLOAN is a graduate stu­ and genetic variants in determining genetics approach that combines dent; VICKI SAYARATH, M.P.H., R.D., is alcoholism susceptibility. To date, some genomics2 and proteomics3 data with research director, Section of Epidemiology of these studies have identified potential methods to understand how biologi- and Biostatistics, Department of susceptibility genes. However, the com- cal processes work together to deter- Community and Family Medicine, plex etiology of alcoholism lends itself mine human health. This approach Dartmouth Medical School; and JASON to further investigation that takes into does not, however, negate the need to H. MOORE, PH.D., is an associate account the multiple layers of interac- look for variants that directly impact professor of genetics and director of the tion between genes within the context disease independent of interaction Computational Genetics Laboratory, of both the genome and environment. effects (main effects) within the data. Departments of Genetics and Community Systems genetics offers a new A complete review of all results and Family Medicine, Dartmouth approach to studying the progression from genetic, genomic, proteomic, Medical School, Lebanon, New Hampshire. 14 Alcohol Research & Health Systems Genetics based on biochemical evidence for ics plays in alcoholism and then gives and cytochrome P450 2E1 (CYP2E1). their role in disease (i.e., candidate a brief overview of the key findings ADH is responsible for 80 percent of genes) and genome-wide studies, from candidate gene and genome-wide ethanol’s metabolism to acetaldehyde, followed by an overview of the inter­ studies. These studies confirm the role which is then further metabolized to action among genes (i.e., epistasis) of genetics in the development of acetate by ALDH. CYP2E1 metabo­ and its current and potential applica­ alcoholism and elucidate the need for lizes approximately 10 percent of tion in the study of alcoholism. This a systems-based approach to the study ethanol and, because of its lower article concludes with a discussion of of the genetic basis of the disease. affinity for ethanol, is largely active several methods currently being devel­ only when ADH is saturated (Gemma oped that incorporate a systems approach Candidate Gene Studies et al. 2006). to genetics and their potential applica­ Researchers also have studied various tions for the future study of alcoholism. Two basic strategies are used to iden­ genes related to the brain chemistry tify genetic risk factors for common of alcoholism and specific chemicals human diseases. The most common (i.e., neurotransmitters) involved in Alcoholism Genetics: approach is to focus on a few candi­ addiction. Such research has exam­ A Brief Overview date genes. This targeted approach ined genes for the binding sites (i.e., is popular because a biological basis receptors) for the neurotransmitter The genetic architecture of suscepti­ exists for the hypotheses being tested. gamma-aminobutyric acid (GABA); bility to a disease such as alcoholism Alternatively, genetic variations (i.e., opioid receptors; components of the can be defined as (1) the number of polymorphisms) from across the human pathways for the neurotransmitters genes directly or indirectly involved, genome can be measured in a high- serotonin, dopamine, and glutamate, (2) the interindividual variation in throughput manner to search for as well as the enzyme catechol-O­ those genes, and (3) the magnitude genetic risk factors without making methyl-transferase (COMT), which and nature of their specific genetic assumptions about which genes might is involved in the inactivation of effects. Alcoholism develops in sus­ be important. This latter genome-wide dopamine; and the neurotransmitter ceptible individuals as a result of approach is popular because much neuropeptide Y (NPY) (Dick and Bierut genetic, environmental (e.g., alcohol more information is examined. 2006; Oroszi and Goldman 2004). consumption), and social influences, Researchers frequently debate the Candidate gene association studies as well as their propensity for risk- advantages and disadvantages between also help to focus on genetic variants taking behaviors (Ramoz et al. 2006). candidate gene and genome-wide that may be directly linked to patho­ Because of this complex etiology, strategies as well as the differences in physiology, as reviewed by Kohnke multiple levels of information must genome-wide strategies themselves. (2007). Several genes, including those be integrated to more completely Risch (2000) suggests that genome- for neurotransmitters such as dopamine understand the genetic architecture wide association studies, which com­ as well as those genes mentioned above, of alcoholism. In the progression of pare the genomes of people with an have undergone frequent investigation multifactorial diseases such as alco­ illness (i.e., cases) with unaffected in candidate association as well as link­ holism, gene–gene interactions result people (i.e., controls), may be more age studies. Some have shown promis­ in a variety of differentially expressed sensitive toward finding effects for ing, and others conflicting, results. proteins. These proteins also interact, complex diseases than genome-wide The candidate gene approach has resulting in certain biochemical and linkage studies, which seek to identify not only confirmed a genetic compo­ physiological characteristics that, in regions of the genome that are associ­ nent of alcoholism but also has the presence of certain environmental ated with disease risk. The candidate brought important understanding to influences, result in alcoholism. gene approach is more direct and disease etiology and may yield further Although studies of alcoholism’s hypothesis-based and, therefore, per­ insight when integrated with gene etiology have been successful in iden­ haps more likely to have significant expression and proteomic analysis. tifying