This chapter examines the evidence from family or genetic high-risk studies in schizophrenia, an example of a highly heritable, complex neuropsychiatric disorder for which the aetiology and pathophysiology remain elusive. It discusses a rationale for using family/genetic high-risk studies and the concept of endophenotypes. Emphasising applications in schizophrenia research, Gottesman and Gould provide compelling evidence to suggest that further study and identification of endophenotypes hold tremendous promise for clarifying the aetiology and pathophysiology of schizophrenia, and improving its treatment. In addition to the endophenotypes, measurement of olfactory functioning is independent of diagnosis and hence provides a feasible approach, both practically and economically, for assessing abnormal brain function and genetic vulnerability to schizophrenia. Continued investigations of the olfactory system and related abnormalities, and particularly its role as an endophenotype, may aid in unravelling the mysteries of the molecular and genetic underpinnings of schizophrenia and other complex neuropsychiatric diseases.

This chapter reviews the several approaches to investigate premorbid risk for schizophrenia. It presents a critical appraisal of the existing studies focusing on the populations at risk for schizophrenia, the issues surrounding study design, predictive and outcome factors identified so far, and the timing of the studies. Studies of premorbid risk, risk for schizophrenia and prospective studies have utilized genetic propensity, neurobehavioral markers, or psychopathology to identify the risk status. The chapter outlines the potential merits and disadvantages of these strategies, reviews the lessons learned from the early first high-risk (HR) studies and presents a rationale for more focused next-generation studies to examine premorbid risk. Recent advances in developmental neurobiology and neuroscience make it reasonable to expect a paradigm shift in research on schizophrenia. It is hoped that the third millennium will usher in a new generation of research studies on high-risk (HR) populations.