Genomics of Behavioral Diseases

Interactions between endogenous factors, e.g., gene allelic variants, and exogenous factors, e.g., exposure to specific environments, can be reasonably suspected as the cause of the most common chronic communication disorders. However, the elucidation of genetic factors and their interactions with non-genetic factors in behavioral diseases has been challenged. To date, two main strategies have been used for the identification of genes for diseases of unknown molecular etiology. Over two decades, linkage analysis and positional cloning of the disease gene were effective in the identification of genes for Mendelian or monogenic single-gene disorders (Botstein and Risch, 2003; McKusick, 2007). The methodological and statistical threshold criteria, applied for linkage analysis in families, provides robust evidence for identification of chromosomal locus and the gene mutation characterized by high penetrance. Among common neuropsychiatric diseases, the approach was successful in the identification of genes for familial early onset Alzheimer’s disease (AD) carrying autosomal-dominant mutations in PSEN1, PSEN2 genes (Rogaev et al., 1995; Sherrington et al., 1995). Another genetic approach, genome-wide association (GWA), or direct genetic association analysis in candidate-genes, employs relatively common genetic variations across the genome or in selected genes for comparative analysis in case–control groups. GWA has been applied for hundreds phenotype traits, including neuropsychiatric conditions (Wellcome Trust Case Control Consortium, 2007; Donnelly, 2008). The genetic association methodology generated much more controversial data in interpretation (Pearson and Manolio, 2008). In most cases, the GWA studies identified only a minor proportion of genetic contribution to common illnesses with little medical diagnostic value. Nonetheless, the genetic association method revealed some convincing data. For example, as confirmed in numerous studies, ApoE ε4 allelic isoform is a common risk factor for AD in ethnic groups of Caucasian and Asian origin. Analysis of two large Caucasian cohorts stratified by age showed that the ApoE-genotype dependent lifetime risks for AD are similar to those of Mendeliandisease genes with major risk effect (Genin et al., 2011). Unlike AD, however, no mutant gene convincingly inherited as a Mendelian trait has yet been described for schizophrenia and affective disorders, despite the fact that many mutigenerational pedigrees are available. GWA employs relatively common single-nucleotide polymorphisms (SNPs) across the genome. The recently emerged concept that rare genetic variations, rather than common population variations, underlie common diseases challenges the standard genetic association approach in neuropsychiatric genetics.