Review article
Neuropsychopharmacology and the genetics of schizophrenia
A history of the diagnosis of schizophrenia
Thomas A. Ban
Department of Psychiatry, Vanderbilt University, Nashville, TN, USA
Accepted 10 May 2004 - Available online 25 July 2004
4. Genetics
Confirmation of Mendel's (1866) law of heredity independently in 1900 by de Vries, Correns and Tschermak (Garrison, 1960) triggered interest in genetics, the scientific study of heredity. In the eighth edition of his textbook, Kraepelin (1913) noted that about 70% of his patients with dementia praecox at the Heidelberg Clinic (1891–1899) had a family history of psychosis (Shorter, 1997). His findings set the stage for research in the genetics of the disease.
Findings in family studies are consistent with a genetic etiology of schizophrenia. The risk of developing schizophrenia was found to be consistently higher in the relatives of schizophrenics than in the general population, with the risk for first degree relatives greater than the risk for second degree relatives. In Zerbin-Rudin’s (1967) pooled data, the risk for children of one schizophrenic parent was nearly 15 times higher (12.3%) than in the general population (0.85%); for siblings and parents about 10 times higher (8.5% and 8.2%, respectively); and for uncles and aunts (2%), nephews and nieces (2,2%), grandchildren (2.8) and half-siblings (3.2%), roughly three times higher than the population rate (Tsuang and Vandermey, 1980).
Concordance rates from schizophrenia were found to be higher in monozygotic twin pairs, which have the same genetic constitution, than in dizygotic twin pairs, which have the same genetic relationship as that of ordinary siblings. In the 11 twin studies conducted between 1928 and 1972 (Hamilton, 1976), concordance rates in monozygotic twin pairs ranged from 35% to 69% and in dizygotic twin pairs from 0% to 26%. The mean concordance rate in the pooled data was more than four times higher in monozygotic (55.5%) than in dizygotic (13%) twin pairs.
Findings in four different types of adoption studies are consistent with a genetic etiology of schizophrenia. In one type of adoption study, it was found that significantly more adopted-away children of schizophrenic parents who went into the homes of non-schizophrenic foster parents developed mental illness or schizophrenia spectrum disorders than adopted-away children of normal parents (Heston, 1966; Rosenthal et al., 1968). In another type of adoption study, significantly more subjects with schizophrenia spectrum disorder were encountered among the biological relatives than among the adoptive relatives of schizophrenic adoptees. (Kery et al., 1968, 1971, 1975, 1978, 1994). And in a fourth type of adoption study, there was a significantly higher prevalence of schizophrenia spectrum disorder among children of schizophrenic parents raised by normal adoptive parents, than among children of normal parents raised by schizophrenic adoptive parents (Wender et al., 1974).
In spite of findings in family, twin and adoptive studies, the mode of transmission of schizophrenia has remained hidden (Faraone et al., 1999; O’Rourke et al., 1982). On the basis of a comprehensive review of pedigree and segregation analyses, the Genetic Workgroup of the United States National Institute of Mental Health has concluded that a single major locus cannot account for a large proportion of the familial aggregation of schizophrenia; the Workgroup suggested that the mode of inheritance of schizophrenia is complex and involves multiple interacting genes (Moldin, 1999). Similarly, mathematical analyses suggest that the transmission of schizophrenia is polygenic (Faraone and Tsuang, 1985) and that the effect of any single gene on risk for the disorder is likely to be small (Faraone and Tsuang, 1985; Faraone et al., 2002; Risch, 1990). Gershon and Badner (2001), considering the high concordance rate of schizophrenia in monozygotic twins, and the very much lower relative risks for schizophrenia in more distant relatives, hypothesize that the transmission of schizophrenia is oligogenic, implying that it involves fewer than 10 genes at multiple locations.
Findings in molecular genetic studies did not further understanding about the genetics of schizophrenia. Employment of genome scanning (positional cloning, or backward genetics) yielded inconsistent and conflicting results. In the numerous publication reporting susceptibility loci for schizophrenia on the short and /or long arms of different chromosomes, well over 10 (1p, 3p, 5p, 6p, 8p, 8q, 9q, 10q, 12q, 13p, 14p, 15q, 20p, 22q) genes have been implicated. Nevertheless, since findings in one group of patients could to be replicated in others, it has been suggested that schizophrenia is a genetically heterogeneous mix (Ban, 2002; Strober et al., 2000; Tsuang and Vandermey, 1980).
To reduce genetic complexity, endophenotypes of schizophrenia were identified and studied. These alternative or intermediate phenotypes consist of populations with discrete neurobiological deficits which segregate with schizophrenia and with the genetic risk for schizophrenia (Gershon and Badner, 2001; Weinberger, 2002). In one class of endophenotypes, the impairment of attention a neurobiological deficit, is displayed in difficulties in smooth-pursuit eye tracking (Holzman, 1992; Levy et al., 1994; McDowell et al., 2001) or in suppression of auditory evoked potentials, such as the p50 wave (Adler et al., 1998; Freedman et al., 1999; Freedman and Squires-Wheeler, 1994; Tsuang et al., 2002). In another class of intermediate phenotypes the impairment in prefrontal information processing and executive functions is displayed in changes in catechol-0 methyltransferase (COMT) activity (Weinberger et al., 2001). Each intermediate phenotype is present in a substantial percentage of schizophrenic patients and in many of their unaffected first degree relatives.
Research with endophenotypes has moved the genetics of schizophrenia from the realm of statistics and probabilities to the concrete reality of biological mechanisms of susceptibility (Weinberger, 2002). Arolt et al. (1996) linked abnormal saccadic eye movements (smooth-pursuit eye tracking) with a locus on the short arm of chromosome 6, without identifying the specific gene and the variant allele accounting for the linkage. Freedman et al. (1997) linked the abnormal P50-evoked potentials with a locus on the long arm of chromosome 15, which overlaps with the gene for the alpha-7-nicotinic receptor. Egan et al (2001) identified a variant (val allele) in the DNA sequence of the COMT gene responsible for the decrease of prefrontal dopamine function with a consequent decrease of cognition (Weinberger, 2002). Nevertheless, the relevance of findings with alternative phenotypes to the genetics of schizophrenia has been questioned because abnormal saccadic eye movements and abnormal p50-evoked potentials are encountered several times more frequently in the general population than schizophrenia (Faraone et al., 1999), and variations in COMT activity account only for a very small percentage (about 4%) of the variation in executive cognition in normal human beings (Weinberger, 2002).