Smoking is perhaps the foremost public health challenge in the United States and in the world. In a series of rapidly emerging studies, we and others have demonstrated that cigarette smoking is associated with changes in the DNA methylation signature of peripheral blood cells. The changes associated with this type of substance use are both dose and time dependent. These changes in DNA methylation are also accompanied by changes in gene transcription and protein expression whose patterns are furthermore indicative of increased vulnerability to other forms of complex illness. In the past, our efforts to translate this knowledge into actionable information has been stymied by a lack of methods through which to systematically to assess these changes. The rapid advance of DNA methylation assessment technologies changes that dynamic and presents the possibility that methylation-based clinical tools to aid the ascertainment of smoking status or effectiveness of treatment can be developed. In this chapter, we will review the latest advances in this field and discuss how these advances allow us insight as to methods through which to prevent smoking and shed insight into optimizing strategies through which to identify biomarkers for other behavioral illnesses which share similar contributions from environmental and gene- environmental interaction effects.

The concepts and investigations reviewed above suggest the following * Schizophrenia is a clinical syndrome that can be deconstructed into meaningful domains of psychopathology. * Individual patients vary substantially on which domains are present as well as severity. * Negative symptoms are common in persons with schizophrenia, but only primary negative symptoms are a manifestation of schizophrenia psychopathology in the "weakening of the wellsprings of volition" sense that Kraepelin described. * The failure to distinguish primary from secondary negative symptoms has profound consequences as viewed in the vast majority of clinical trials that report negative symptom efficacy without regard for causation and without controlling for pseudospecificity. * Schizophrenia is now broadly defined with positive psychotic symptoms, and a subgroup with primary negative symptoms is a candidate disease entity. * Evidence of negative symptoms as a taxon supports the separate classification of persons with primary negative symptoms. * Negative symptoms are an unmet therapeutic need. * Two factors best define the negative symptom construct and these may have different pathophysiological and treatment implications. * The avolitional component may not be based on a diminished capacity to experience pleasure, but difficulty using mental representations of affective value to guide decision-making and goal-directed behavior. Part II in this volume by Strauss et al. will address the range of laboratory-based investigations of negative symptoms, clarify current hypotheses and theories concerning negative symptom pathology, and address future directions for negative symptom research and clinical care.