Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

299 Challenges in the genetics of bipolar disordermicroarray techniques that can detect tissue-specific expression, transgenic mice,expression arrays, and proteomics, allowing identification of gene function, willenhance our knowledge of the biologic significance of gene markers. Parallelresearch across numerous species will provide important information regardinggene expression, phenotypic models, and gene–environment interaction (Peltonenand McKusick, 2001). Knowledge of gene function and regulation is likely to lead toa shift from reverse-genetic approaches (linkage and linkage disequilibrium analysis)to forward-genetic approaches (Risch, 2000).Similar progress in neuroscience, particularly developmental neuroscience, whichinvestigates molecular, cellular, and integrative brain functions involved in the developmentof mental disorders, will advance our understanding of the complex biologicprocesses underlying mental disorders. The tools of neuroimaging, psychophysiology,and preclinical models of emotion are likely to provide information on etiologicpathways to mental disorders. Likewise, the impact of environmental exposures onmodifying the development of cognition, emotion, and activity level will provide newopportunities to investigate mechanisms underlying gene–environment interactionsinvolved in mental disorders. Greater understanding of the biologic and contextualfactors from which mental disorders arise will dramatically improve the power ofgenetic studies to close the gap between the phenotype and genotype.As we move from single-gene disorders to complex disorders, new tools will benecessary to reflect the multiple interacting factors. Increasingly, statistical methodswill be based on the biological significance of markers, and new models will beemployed to identify gene clusters, expression profiles, haplotype sharing, geneticattributable risk, and direct assessment of gene–environment interactions. Themajor focus on genetic studies will shift from a search for the gene, to which genesin which contexts lead to the development of mental disorders. The highlyrestricted sampling of the earlier generation of studies is likely to move into thegeneral population where the concept of attributable risk will become salient.Finally, the dramatic developments in molecular genetics and new approachesto sampling and gene detection will require substantial focus on ethical issuesrelevant to subject recruitment and interpretation of genetic data. Education ofprofessionals involved in genetic research as well as those involved in the disseminationand interpretation of genetic marker data will be critical to ensure theethical application of genetics to complex diseases in general and psychiatricdisorders specifically. The assurance of truly informed consent will require comprehensionof a risk-factor approach to genetics with respect to the concepts ofabsolute, relative, and attributable risk. Professional education should then befollowed by public education in order for the public to gain an understanding ofthe meaning of genetic markers in disease prediction. Ironically, the public tendsto attribute far greater significance to genetic markers than has been realized for