There is strong evidence from family, twin, and adoption studies that a genetic vulnerability underlies schizophrenia (Gottesman & Shields, 1982
; Lowing et al, 1983
; Kendler et al, 1985
). The principal challenge now is to locate and identify major genes that may predispose to this vulnerability. To this end, genetic linkage studies are underway around the world. However, many difficulties face researchers in this area, both in the initial search and in confirmatory studies (Bassett, 1989
). There is a single positive report of linkage to date, linking schizophrenia to DNA markers from chromosome 5q (Sherrington et al, 1988
). Researchers studying other families (e.g. Kennedy et al, 1988
; St Clair et al, 1989
) have not replicated this result. Given the likelihood that several major genes predispose to schizophrenia, a method to help maximise the probability of finding such genes would be valuable.
One approach to investigating specific genetic involvement in psychiatric disorders is to identify associated chromosomal abnormalities. Chromosomal aberrations associated with psychiatric disorders may suggest regions in which to focus the initial search for disease-causing genes by a genetic linkage strategy. As for other illnesses, such as neurofibromatosis, chromosomal abnormalities may also provide useful tools for subsequent physical mapping, fine localisation, and isolation of important susceptibility genes. Identification of several chromosomal aberrations may be especially important given the unknown pathophysiology, the paucity of known brain genes, and the probable genetic heterogeneity of major psychotic illnesses.
Chromosomal abnormalities associated with various genetic disorders have proven valuable for localising and isolating causative genes (). The fortuitous observation of these rare events has substantially aided in, for example, the physical mapping and subsequent cloning of the gene causing Duchenne muscular dystrophy (DMD) (Ray et al, 1985
). In addition, associations of specific diseases with chromosomal aberrations have suggested candidate regions for linkage studies. A complex unbalanced translocation involving a partial trisomy of the long arm of chromosome 11, observed in a neonate with cardiac rhabdomyoma (Clark et al, 1988
), focused the search for a tuberous sclerosis (TS) gene on the 11q23 region, although positive linkage to the ABO locus on chromosome 9 had already been found in some families (Fryer et al, 1987
). Researchers subsequently reported significant linkage of TS to markers from 11q22–11q23 (Smith et al, 1990
Examples of chromosomal abnormalities aiding gene localisation
Chromosomal abnormalities have also provided important clues to the genetic cause of behavioural disorders. Many patients with Prader-Willi syndrome (PWS), a hypothalamic disorder leading to behavioural disturbances, with onset in adolescence, have small deletions of the long arm of chromosome 15 (Mattei et al, 1984
). PWS is more complex than this, however, as the Prader-Willi deletion chromosome is almost always paternally inherited, and similar deletions when maternally inherited cause Angelman syndrome (Knoll el al, 1989
). This suggests that genetic imprinting may be an important phenomenon in some chromosomal abnormalities. Imprinting may also be important in disorders lacking a clear pattern of inheritance (Hall, 1990
Unlike simple Mendelian conditions such as DMD and TS, the major psychotic disorders, schizophrenia and manic-depression, are complex genetic conditions. Like hypertension or diabetes mellitus, major psychotic disorders may have several important genetic and non-genetic factors that predispose to the illness, either individually or in an interactive fashion (Risch, 1990
). The pathophysiology of schizophrenia and manic-depression is unknown, and researchers have identified relatively few of the up to 100 000 brain-related genes which, in a broad sense, could all be considered candidate genes. These problems make linkage analysis of psychiatric illness challenging, and a complementary strategy for finding major susceptibility genes more important.
There are few reviews of chromosomal abnormalities and psychiatric disorders in the literature. Chromosomal abnormalities may involve either the sex chromosomes (X and Y) or the autosomes (chromosomes 1–22). Propping (1983)
tabulated three chromosomal abnormalities associated with possible schizophrenia-like psychoses: XXY, XXX, and 18q- or ring 18. More recently, in the context of their own cytogenetic survey of 46 men with schizophrenia, DeLisi & Lovett (1990)
summarised 15 X chromosome studies and four reports of autosomal abnormalities associated with psychoses. Crow (1988)
has also examined sex chromosomes and psychotic disorders, an important area with numerous reports dating back to 1962, deserving its own critical review. The focus in the current paper, however, is restricted to autosomal abnormality associations, which have been less discussed than the sex chromosomal anomalies. The present review updates and extends the references catalogued in the Propping (1983)
and DeLisi & Lovett (1990)
articles, and critically reviews the evidence for reported associations of autosomal abnormalities and psychiatric illness. The relevance of these associations for genetic linkage studies was estimated with standardised criteria for specificity, diagnosis, family history, and overall weight of evidence. The results of this critical review suggest strategies for future studies to detect new chromosomal aberrations associated with major psychotic disorders that may be relevant to isolating a gene for schizophrenia.