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Blind alleys, acts of faith, and difficult science
Perhaps the greatest set of challenges facing clinical science is to discover the molecular bases of common disorders such as diabetes, coronary heart disease, cancer, Alzheimer's disease, and the functional psychoses. Molecular genetic techniques have been dramatically successful in single gene disorders, which are usually fairly rare. Common familial diseases, however, provide greater problems because of their complex and non-mendelian patterns of transmission.
Nowhere are the difficulties greater than in the study of schizophrenia; here, without objective laboratory tests, we are forced to rely on clinical signs and symptoms, which are often unstable, and on diagnostic schemes, which, though now highly reliable, have no proved validity. Nevertheless, the evidence from family, twin, and adoption studies for an important genetic component is compelling and has persuaded many researchers that the time has come to tackle the aetiology of schizophrenia at a molecular level.
The strategies being adopted can be conveniently divided into two--the "positional cloning" and the "candidate gene" approaches. Positional cloning describes a set of techniques by which disease genes are identified through their position in the genome rather than through their function. In its initial stages the approach relies on linkage analysis, which seeks to find cosegregation of genetic markers with the disease in question in multiply affected families. Clues about where to begin in the search for linked markers may be provided by cytogenetic abnormalities.
For example, the finding of an apparent relation between partial trisomy of the long arm of chromosome 5 and schizophrenia in a Canadian-Chinese family followed by a report of linkage between schizophrenia and DNA markers in the 5q11-q13 region seemed to provide a breakthrough. Unfortunately, other …