ture and function, producing much more subtle effects. For example, many of the genetic variants that have been associated with MEB disorders are single nucleotide polymorphisms, that is, substitutions of single nucleotides, the structural components of the genetic sequence (van Belzen and Heutnik, 2006; Sanders, Duan, and Gejman, 2004). Variability in the number of copies of a specific gene sequence (known as copy number variants), which can be caused by rearrangements, microdeletions, or microduplications of the sequence, has also emerged as an important contributor to MEB disorders (Lee and Lupski, 2006), such as schizophrenia (Walsh, McClellan, et al., 2008; Xu, Roos, et al., 2008; International Schizophrenia Consortium, 2008; Stefansson, Rujescu, et al., 2008) and autism (Sebat, Lakshmi, et al., 2007; Marshall, Noor, et al., 2008). These kinds of gene variations can have a more graded influence on molecular and cellular functions than do large deletions or rearrangements of genes. The influences of these gene variants on the structural and functional features of cells, neural circuits, and the behaviors they subserve are correspondingly graded as well.
Variations in the genetic sequences that encode proteins are only one level of influence on the expression of those genes in the production of cellular proteins. Variations in the sequence of the nonencoding, regulatory portions of a gene also have important influences on its expression, as can variations in other genes that encode regulatory proteins. In addition, microRNAs (small sequences of RNA, an intermediate genetic component in the process of making proteins from DNA) can influence the expression of genes and their protein products by altering how the proteins are generated from a gene sequence (Boyd, 2008; Stefani and Slack, 2008). These additional levels of regulation can determine when in the course of development, where in the brain, and to what degree a gene is expressed—all without changing the DNA sequence of the gene.
Many studies, including family studies and gene association studies, have demonstrated a genetic component to MEB disorders (Thapar and Stergiakouli, 2008; van Belzen and Heutnik, 2006). However, genetic studies have not yet found an association of single genes with most MEB disorders. Instead, sequence variants in multiple genes have been shown to be associated with an elevated risk or susceptibility for developing many diseases, such as autism (Muhle, Trentacoste, and Rapin, 2004), depression (Levinson, 2006; Lopez-Leon, Janssens, et al., 2008), schizophrenia (Owen, O’Donovan, and Harrison, 2005), addiction (Goldman, Oroszi, and Ducci, 2005), and bipolar disorder (Serretti and Mandelli, 2008). A review of these many reported associations of specific genes with individual disorders is beyond the scope of this report.
In nearly all instances of these reported associations, the influence of individual genes on the risk for developing a disorder is small (Kendler, 2005; Thapar and Stergiakouli, 2008), usually less than the influence of