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The goal of this section is to provide an overview of the current state of knowledge regarding the genetics of schizoprenia. The discussion will focus on the following key question : Is schizoprenia a familial disorder? To what extent is any familial aggregation of schizoprenia due to genetic versus enviromental factors? How narrow or broad are the psychiatric disorders that are transmitted within families? Because genetic factors play an important role in the familial transmission of schizoprenia, the following additional question are also pertinent : What is the current status of and the future prospects for identifying specific genes that prespose a person to schizoprenia.
IS SCHIZOPRENIA FAMILIAL ?
In a 1967 review paper Edith Zerbin- Rudin listed 17 major family studies of schizoprenia involving first – degree relatives. By 1980 at least nine other major family studies had been reported. Parental relationships are exceptional and are not considered here because it is well established that persons affected by schizoprenia exhibit reduce fertility. Since, by definiton , a parent must have succesfully reproduced at least once, parents of schizoprenic offspring are less likely to have expressed the symptoms of the disorder, despite carrying predispoding risk factors that may have been transmitted to their offspring. Aside from parental relationships the studies consistently showed a much greater risk for schizoprenia in the close relatives of schizophrenic persons than would be expected in the general population.
However, nearly all studies suffered from three important methodological limitations. First, no contrl groups were used, so the rates of schizophrenia in the general population required for comparison had to be derived from literature. Second, diagnoses were made nonblind, with the investigator or coworkers always knowing that the person evaluated was a relative of a schizophrenic person. Third, neither structured personal interviews nor operationalized diagnostic criteria were used. In fact in many of the early studies it is unclear how many persons were personally examined and now how many were evaluated from indirect information such as reports of relatives or doctors, or from hospital notes.
Persons with schizoprenia seem to inhert a predisposition to the disorder. Their relatives have a greater incidence of schizoprenia than chance alone would allow. The genetic risk for schizoprenia is shown in Box 23. 6
Genetic Risk for Schizoprenia
Identical twin affected 50%
Fraternal twin affected 15%
Brother or sister affected 10%
One parent affected 15%
Both parents affected 35%
Second-degree relative affected 2-3%
No affected relative 1 %
Of particular interest to clinicians is the risk associated with having a parent afflicted with schizoprenia ( Rosen, 1978 ) , this higher incidence alone does not adequately address the nature ( genetics ) vs nurture ( upbringing ) debate. For instance, a mentally disordered parent may rear children so inadequately that children are predisposed to schizoprenia in the basis of the parenting skills, not genetics.
To control the “ nurture “ variable, reseachers have studied twins. Both monozygotic ( identical ) and dizygotic ( fraternal ) twins have been studied. Monozygotic twins have cnsistently reported a higher concordancy rate ( meaning both twins do or do not have symptoms of schizoprenia ). Concordancy rates are 50% for monozygotic twins. This is 50 times greter than the risk for the general populations, and three times higher than the risk for dizygotic twins.
These findings seem to establish the genetic or nature basis of schizoprenia ; however , there are still extraneous variables that cannot be explained. For instance, many monozygotic twins are dressed alike and often are misidentified; their upbringing is identical, too. Some argue that it is no wonder that monozygotic twins have a high concordancy rate. Unless researchers can control the enviroment variable, the relative impact of nature and nurture cannot be reported with confidence.
To control for the variable of enviroment, studies have been conducted of situations in which monozygotic twins have been separated at birth and reared apart. Monozygotic concordancy rates remain significantly higher in these studies.
Even before birth, a child may have genetic characteristics that presdispose him or her to schizoprenia. The evidence from classic clinical studies for a genetic contribution to schizoprenia is well documented. Studies of families, twin, and adopted chlidren have shown a familial risk for schizoprenia and nonaffective psychosis ( Cloninger , 1989 ). According to these studies, first degree relatives ( i.e., mother, father, sister, brother, or child ) of a person with schizoprenia have approximately a 10 percent chance of developing the illness as compared with a 1 percent chance for the general population.Second – degree relatives ( e.g ., granddaughter or niece ) have a 2 to 4 percent chance ( Costa, 1992 ). Non affective disorders, including schizoaffective and paranoid disordersand cronic atypical cases, are also associated with a higher risk factor ( 7.8 percent ) for relatives than for nonrelatives ( Cloninger, 1989 ).
Twin studies have cnsistenly demonstrated a high rate of concordance for schizoprenia. If one monozygotic ( genetically identical ) twn has schizoprenia, studies have found that 46 to 48 percent of the co – twins are likely to have the illness , compared with a concordance rate of only 14 to 17 percent for dizygotic twins who share about half of their genes ( Andreasen & Black, 1991 : Bracha et al., 1992 ). There is some envidence for genetic cause, yet the result are not 100 percent in monozygotic twins ( Table 12-1 ). Murray and Harvey ( 1989 ) indicated a correlation in liability in first degree relatives when they compared the estimate of likelihood for schizoprenia ( 0.37 to 0.43 ) with thar for diabetes ( 0.27 to 0.40 ), coronary artery disease ( 0.33) and hypertension ( 0.24 ). These data place the risk factors for schizoprenia into a better perspective with other disease. Kety’s adoptive studies in Denmark were intended to separate the effects of rearing from those of genetics. These studies showed that the risk for schizoprenia is higher in biological relatives than in adoptive relatives ( Gottesman, 1991)
Genetic Risk Factors for Schizoprenia
STATUS RISK ( % )
First-degree relatives ( mother, father, sister, brother, child ) 10%
Second-degree relatives ( granddaughter,niece,nephew ) 2-4
Monozygotic twins ( genetically identical ) 46-48
Dizygotic twins ( share half their genes ) 14-17
Other genetic hypothese are under investigation. Genes involved in the immune process, such as human leukocyte antigen complex chromosome 6 , have been considered ( Cloninger, 1989 ) because of repeated observations that rheumatoid arthritis and paranoid schizoprenia seldom occur in the same person. A recent study reported that children of mothers exposed to an influenza epidemic during the second trimester of pregnancy were at increased risk for developing schizoprenia ( Mednick et al.,1988 ) , however there is no direct evidence that such viral infections alone are sufficient to cause schizoprenia. Bruton et al. ( 1990 ) presented the possibility of a defect in cell proliferation in the developing brain, particularly effecting hippocampal formation ( SEE Fig.12-1 ) . This theory is supported by computed tomography ( CT ) scan evidence of a decreased number of cells in the hippocampus in some people with schizoprenia. Another factor in understanding the genetics of schizoprenia is the possibility that there is no gene to code negative symptoms. Instead, reseachers may find a defective neurodevelopmental pattern that result in a set of structural changes that predispose a person to schizoprenia.