CLINICAL HANDBOOK OF SCHIZOPHRENIA

56 I. CORE SCIENCE AND BACKGROUND INFORMATIONTABLE 6.1. The Chain of Psychiatric Genetic ResearchQuestionAppropriate methods1. Does the phenotype run in families? Family study2. What are the contributions of genes and environment? Twin study, adoption study3. What is the mode of transmission? Segregation analysis4. Where are the genes located? Linkage analysis5. What are the responsible genes? Association analysis6.1 represent a sampling of the most popular and powerful methods available for answeringthese fundamental questions in the chain of psychiatric genetic research.RESEARCH METHODSPsychiatric genetics is a multidisciplinary field whose roots in psychiatry, human genetics,statistics, and epidemiology date back nearly 100 years. The earliest work on schizophreniainvolved clinical and behavioral genetic methods such as family, twin, and adoptionstudies, and segregation analyses, which are effective for establishing whether, to whatdegree, and in what manner genetic factors influence the disorder (questions 1–3 in Table6.1). Subsequently, the field branched out to include molecular genetic methods thatcould enable the isolation of chromosomal regions and identification of specific genesmediating familial transmission of schizophrenia through linkage and association analyses(questions 4 and 5 in Table 6.1).Question 1: Is Schizophrenia Familial?The first question that must be answered when attempting to delineate the genetic andenvironmental components of a disorder is, “Does the phenotype run in families?” or “Isthis phenotype familial?” This question can be answered through the use of family studies.The basic design of the family study begins with the ascertainment of a group of subjectsthat is affected with schizophrenia (cases) and a comparable group of control subjectswho do not have the disorder. Next, the biological relatives of these index subjects, orprobands, are ascertained and evaluated for the presence of schizophrenia. The rate of thedisorder among family members of affected probands is then compared to the rate of thedisorder among family members of control probands to determine the familial risk, orrelative risk. In a family study, or in any of the other genetic studies described in thischapter, it should be recognized that schizophrenia can be defined by the presence of formaldiagnostic criteria or, for research purposes, alternative classification schemes (e.g.,schizophrenia spectrum disorders) may be used to maximize inferential power.If schizophrenia has a genetic etiology, then biological relatives of cases should havea higher likelihood than relatives of controls of carrying the gene or genes that influencedillness in their relative; thus, they should be at greater risk for the illness themselves. Inaddition, the risk to relatives of cases should be correlated with their degree of relationshipto the proband, or the amount of genes they share in common. First-degree relatives,such as parents, siblings, and children, share 50% of their genes, on average, with theproband. Thus, first-degree relatives of cases should be at greater risk for the disorderthan second-degree relatives (grandparents, uncles, aunts, nephews, nieces, and half-siblings),because second-degree relatives share only 25% of their genes with the proband.