Neuropsychopharmacology: The Interface Between Genes and Psychiatric Nosology

By Thomas A. Ban

3.GENETICS IN PSYCHIATRY

3.1 EPIDEMIOLOGICAL GENETICS

The notion that mental illness runs in families was endorsed by Kraepelin (1896) and Magnan (1896). It received substantial support from "family," "twin," and "adoption" studies. The majority of epidemiological genetic studies dealt with Kraepelin's (1899) diagnostic concepts of "manic-depressive insanity" and "dementia praecox." Magnan's (1893) diagnostic concept of "delusional psychoses" received relatively little attention in genetic research.

The risk of developing schizophrenia for relatives of schizophrenics, and manic-depressive illness for relatives of manic-depressives, was found to be consistently higher than in the general population. The risk of developing the respective illness in both diagnostic groups was found to be higher for first than for second degree relatives (Kay 1978; Slater and Cowie 1971).

Concordance rates for schizophrenia, and manic-depressive illness were found to be consistently higher in "monozygotic" than in "dizygotic" twins, with concordance rates in schizophrenia ranging from 35% to 85.8%, and in manic-depressive illness from 33% to 93%. Concordance rates in "dizygotic" twins in schizophrenia ic-depressive illness from 0 to 8%(Gottesman and Shields 1966; Tsuang and Vandermey 1980).

            Children of schizophrenic natural (biological) parents adopted into the homes of non-schizophrenic foster parents were found to develop schizophrenia at a much higher rate than “adopted away” children of normal parents (Heston m1966; Mendlewicz and Rainer 1977). Mnetal illness was found to be encountered at a much higher rate in the biological than in the adoptive families of adopted schizophrenic and manic-depressive children (Kety et al. 1994; Wender et al. 1986).

3.2 MATHEMATICAL MODELS OF INHERITANCE

In spite of findings that genetic factors play an important role in the etiology of schizophrenia and manic-depressive (bipolar) illness, the mode of transmission of these disorders, even with the employment of powerful statistical models, has remained hidden (Craddock et al. 1995; O'Rourke et al. 1982). On the basis of a comprehensive review of findings in "pedigree and segregation analyses," the Genetics Workgroup of the National Institute of Mental Health of the United States concluded that a "single major locus" cannot account for a large proportion of the "familial aggregation" of either schizophrenia or bipolar illness (a term used for manic-depressive disorder), and suggested that the mode of inheritance of these disorders is "complex" and very "likely involves multiple interacting genes" (Moldin 1999).

3.3 MOLECULAR GENETICS: LINKAGE ANALYSIS

Findings in "molecular genetic" studies in schizophrenia and manic-depressive illness lid not clarify matters further. Employment of “positional cloning” (“backward genetics”, “genome scanning”) yielded inconsistent, conflicting results.

There are numerous publications reposting susceptibility loci for schizophrenia on chromosomes 1q, 3p, 5q, 6p, 8p, 9p, 10q, 12q, 13p, 14p, 15q, 20p, or 22q, and for manic-depressive illness on chromosomes 4p, 5p, 6p, 10q, 11p, 12q, 16p, 18p, 18q, 20p, 21q, or 22q. However, the findings in one group of patients could not be replicated in others (Cershon et al. 1998; Moldin 1999).

Different findings in different samples from the same diagnostic category indicate genetic heterogeneity within the diagnosis (Tsuang and Faraone 1990, 1995) However, the heterogeneity, which precluded meaningful genetic research, has not interfered with the recognition that "genetic anticipation," the essential feature of the first genetic theory of mental illness, is encountered in some schizophrenic families and also in some families with manic-depressive illness. Genetic anticipation may result from "trinucleotide repeat mutations," an anomaly, causally linked with Huntington disease (Faraone, Tsuang and Tsuang 1999; Petronis and Kennedy 1995).

3.4 MOLECULAR GENETICS: CANDIDATE GENE APPROACH

Genetic heterogeneity, coupled with heterogeneity in pharmacological responsiveness, has also precluded meaningful research with the employment of "forward genetics" in schizophrenia and manic-depressive illness. Nonetheless, on the basis of the demonstrable therapeutic effectiveness of some psychotropic drugs in schizophrenia and of some other psychotropic drugs in manic-depressive illness, various genes, encoding transporters, receptors, (e.g., serotonin-5HTT, serotonin-5HT2A, dopamine-DRD2, dopamine-DRD3, dopamine-DRD4, dopamine-DAT1), and enzymes (e.g., monoamine oxidase, dopamine-beta-hydroxylase, catechol-O-methyl- transferase) involved in neuronal transmission have been implicated by neuropharmacological research in the pathophysiology of these disorders. "Association studies," with the employment of the "candidate gene approach," however, have invariably failed to detect significant differences in mutations (polymorphisms) in the implicated genes, between normal subjects and schizophrenic or manic-depressive patients (Heiden et al. 2000; Malhotra and Goldman 1999). If there is a difference in "allelic variations" between the treatment responsive form of illness within these diagnostic categories and normal subjects, it is covered up by the heterogeneity of the patient samples used in the comparisons. An essential prerequisite for the demonstration of a difference in "allelic variations" would be the identification of the treatment responsive forms of illness within schizophrenia or manic-depressive illness.

Replication studies also failed to support findings that allelic variations in the serotonin 5SHT2A or S5HT2C receptor genes are - responsible for individual differences in the therapeutic response to clozapine (Arranz et al 1995; Malhotra et al. 1996) If the clozapine responsive form of illness within schizophrenia could be identified, and the difference between the serotonin-5HT2A and dopamine-D2 responsive forms of the illness demonstrated, the question whether therapeutic responsiveness to clozapine depends on “allelic variations" on the serotonin-5HT24 or S5HT2C receptor genes, would become a testable hypothesis.