Schizophrenia
Population Genetics
Family Studies
Pooled family study data from Europe show an age-corrected morbid risk for schizophrenia of 5.6% in parents, 10.1% in siblings, and 12.8% in children. It is thought that the lower rate in parents is related to a relative decrease in fertility among schizophrenic patients. Because general population figures for morbid risk for schizophrenia are around 1%, all classes of first-degree relatives have a clear increase in prevalence. The risk for offspring of two schizophrenic parents is difficult to estimate because of the small number of cases but probably runs between 35% and 45% (in the pooled data it is 46.3%). Among second-degree relatives (eg, uncles, aunts, nephews, nieces, grandchildren), half-siblings, and cousins, the risk ranges from 2% to 4%.
Close relatives of schizophrenic patients are at about a 5- to 10-fold excess risk for the illness, and the risk diminishes in more distant relatives. An additional group of first-degree relatives appear to develop related or so-called spectrum disorders; however, the majority of close relatives of schizophrenic patients are psychiatrically normal.
It is hard to make a strong case for genetic determination of the classical subtypes of schizophrenia (Kraepelin’s hebephrenic, catatonic, and paranoid forms). Although there is significant concordance in MZ twins for subtype, this does not hold true in family studies.
Are schizophrenia and affective disorders truly distinct? Evidence of an overlap in genetic liability was found in a large family study that used lifetime diagnoses and separately examined relatives of control probands and probands who had schizophrenia, chronic schizoaffective disorder, acute schizoaffective disorder, bipolar affective disorder, or unipolar depression. An increase in unipolar disorder was found in all groups of relatives. Relatives of schizoaffective probands (both chronic and acute) showed both an excess of affective disorders and an excess of chronic psychoses, compared to relatives of control subjects. However, bipolar probands did not show an excess of schizophrenic relatives, nor did schizophrenic probands show an excess of bipolar relatives. The most parsimonious explanation of these data is that a “middle” group of disorders (ie, the schizoaffective disorders) is genetically related to both schizophrenia and affective illness and that it may not be possible to completely separate the groups using clinical criteria.
With regard to mode of transmission, results generally favor a multifactorial rather than a single-locus model.
Twin Studies
Twin studies of schizophrenia are summarized in Table 6-8. Several points may be made with reference to these data. First, in each study, MZ twin concordance is greater than DZ twin concordance, an observation that is consistent with genetic hypotheses. Second, the heritability of broadly defined schizophrenia is greater than the heritability of strictly defined schizophrenia. This is consistent with a spectrum concept (ie, some individuals with the genetic loading for schizophrenia manifest a somewhat different condition). Third, the amount of discordance is considerable; even with a broad definition of illness, the total discordance in the twins is 51%.
A series of nine monozygotic twins with schizophrenia who were raised apart from infancy has been reported. Three were regarded as completely concordant, and three were partially concordant. A twin study paradigm has also been used to generate data regarding environmental effects in schizophrenia. Examining age at onset in the Maudsley Hospital twin series, one study found that there was a high incidence of illness in the second of a pair of twins within 2 years of onset of the illness in the first twin. Further categorizing the group on the basis of whether the twins lived together or lived apart, the investigator found the higher incidence to be primarily in those living together. That is, twins living together show concordance in age at onset, whereas twins living apart do not. This is an intriguing finding that suggests an environmental factor.
Adoption Studies
A series of large, systematic studies were based on adoption and psychiatric hospitalization registries in Denmark. In later studies in the series, subjects were interviewed directly. In all studies, adoptees were separated from their biological parents at an early age and adopted by nonrelatives. More schizophrenia and schizophrenia spectrum disorders were present in the biological relatives of schizophrenic adoptees than in the biological relatives of psychiatrically normal adoptees. The prevalences of psychiatric illnesses in adoptive relatives of the two groups were small and comparable.
The frequency of schizophrenia spectrum disorders is higher in adopted-away offspring of schizophrenic parents than in adopted-away offspring of normal parents. These studies have been criticized for the methods used to select subjects, the validity of the diagnoses, and the validity of comparisons. However, further independent analysis of the data has confirmed the essential results: Biological relatives of schizophrenic patients who have not shared the same environment have a significantly higher prevalence of schizophrenia and schizophrenic spectrum disorders than do biological relatives of comparable control groups.
Up to 30% of first-degree relatives of schizophrenic patients have associated disorders. The particular diagnostic categories that seem to be implicated are schizotypal personality disorder, paranoid personality disorder, and schizoid personality disorder. Older studies used the term borderline schizophrenia to include some individuals who had these personality disorders. Other researchers have argued for a separate entity characterized by paranoid delusions only (eg, simple delusional disorder) with inheritance independent of schizophrenia and affective disorder.
Linkage Studies
Reports have implicated loci on chromosomes 22q, 6p and 6q, 8p, 13q, and 10p (Table 6-9). The evidence is strongest for a locus on chromosome 6p. No specific genes have yet been confirmed.
Potential Biological Vulnerability Markers
Certain psychophysiologic abnormalities appear to be genetic vulnerability indicators for schizophrenia. For instance, a deficit in smooth pursuit eye movements (SPEMs) is observed in schizophrenic patients and their relatives. However, there is not a clear differentiation between ill relatives and well relatives: Many well relatives exhibit the SPEM abnormality. Holzman and colleagues formulated what they call the latent trait model to describe the relationship. In this model, a single gene variant may manifest as schizophrenia in some individuals and eye movement dysfunction in others. Family studies are consistent with dominant inheritance. SPEM abnormalities are also observed in some patients who have schizotypal personality disorder.
There are many reports of attentional deficit measures in schizophrenia. Results on the continuous performance test distinguished high-risk offspring of schizophrenic patients from age- and sex-matched control subjects. These young people have now passed through the period of greatest risk for onset of schizophrenia, and about 20% have become psychotically ill.
Auditory evoked potential measures also seem to differentiate high-risk offspring from control subjects. A defect in auditory gating has been described in schizophrenia that may be related to a gene on chromosome 15 that codes for a subunit of the nicotinic cholinergic receptor.
Summary
The heritability of broadly defined schizophrenia approaches 50%. Related disorders appear to include schizotypal and paranoid personality disorders. Psychophysiologic abnormalities are particularly promising as vulnerability markers. Linkage analysis implicates genes on chromosome 6 (perhaps on both 6p and 6q), 8p, and 5q. Additional areas (10p, 13q, 18p, 22q) may be implicated in both schizophrenia and bipolar disorder.
