Genetics and substance abuse disorders

IntroductionSubstance use disorders (SUD) are a significant public health problem in that the lifetime prevalence of alcohol dependence or abuse is 8%, the lifetime prevalence of illicit drug use is 2-3% (1,2), and the lifetime prevalence of nicotine dependence is approximately 25% (3). The cause of these disorders is complex, but it is clear that SUD appear to "run in families", based on the observation that there is a higher frequency of SUD in family members compared to that in controls, and there is a higher frequency of SUD in close relatives compared to more distant relatives (4). Indeed, one family study found that the frequency of SUD in relatives was approximately 8-fold greater than the frequency in relatives of controls or psychiatric patients (5). But how much is attributable to environmental influences vs. genetics? For many years, a number of approaches have been used to separate genetic from environmental effects.Besides family studies, twin and adoption studies have been useful for demonstrating genetic influences on a particular trait. In twin studies, the concordance between monozygous twins is compared to the concordance between dizygous twins; if the monozygous twins are more alike (i.e., more often concordant) than are the dizygous twins, then that would indicate a genetic contribution to the phenotype. For example, for SUD in general, the concordance between monozygous twins has been found to be .63-.77, whereas for dizygous twins it was ,44-.55 (6,7). In adoption studies, if there is a greater similarity between adoptees and their biologic parents than between adoptees and their adoptive parents, that would indicate that there is a genetic component to the phenotype as well (4). Further evidence for a biologic cause for a particular trait or behavior comes from animal studies. In the case of SUD, if laboratory animals voluntarily self-administer some drugs, then that observation provides evidence for a biologic basis for addiction (8).Given these studies, the overwhelming evidence indicates that SUD stem from complex (multifactorial) traits as opposed to monogenic conditions (which are caused by pathogenic mutations with large effect and inheritance patterns that follow autosomal or X-linked, dominant or recessive modes). Complex traits are those presumed to occur because of gene-environment interaction. The genetic component is often referred to as the "heritability" of a trait so that if a trait is said to have a heritability of .5 or 50%, it would indicate that 50% of the variance is attributable to genetic factors. Those genetic factors in turn are generally assumed to originate in multiple genes, each with a small effect, although this may not be universally true.The environmental component can be further divided into shared environment and non-shared environment. For example, siblings raised in the same household have a shared environment. If one of those children, however, was injured in a motor vehicle accident, this would constitute a non-shared environmental effect. In addition, the steps in the progression from non-use to drug dependence are likely under the influence of different degrees of genetic and environmental control. Evidence suggests that environmental factors have a greater influence on the initiation of drug use, whereas genetic factors become more important in the transition to the development of addiction (9,10).So how are genetic studies done? In the past, linkage and association studies identified candidate genes which were likely to be related to a particular phenotype; research would follow looking for a higher frequency of variations in the genes of study subjects versus controls. The use of linkage and association studies, however, depended on an understanding of biologic mechanisms and precise definition of phenotypes. More recently, genome- wide association studies (GWAS) were developed to assay several hundred thousand to a million single nucleotide polymorphisms (SNPs) in populations as large as several thousand individuals. …