Pharmacogenetics and psychopharmacology

Pharmacogenetics and psychopharmacology For more than 40 years, epidemiological studies have clearly demonstrated a tendency for diseases such as schizophrenia, bipolar disorder and autismto run in families. Thus it has been shown that such disorders are much more frequent in close relatives of patients than in the general population. For example, estimates of the increased risk of suffering from the disorder if the patient has a sibling with the disorder range from nine- to eleven-fold for schizophrenia and about sevenfold for those with bipolar disorder. These major psychiatric disorders show a significantly greater concordance rate in genetically identical twins. Thus the concordance rate for monozygotic twins in schizophrenia is approximately three times that observed in dizygotic twins. In bipolar disorder, the corresponding concordance rate is approximately eight times greater in monozygotic than in dizygotic twins. From such studies it has been calculated that between 60 and 80% of the liability of these two disorders is genetic in origin. However, it must be emphasized that these calculations do not identify specific genetic causes for the conditions but they do demonstrate that the genetic, as well as environmental components, play a significant role. The question arises regarding how the genes that contribute to major psychiatric disorders can be identified. Many of the medical conditions for which a genetic component has been identified follow a genetic pattern that clearly follows classical Mendelian inheritance. For example, in cases of Huntington’s disease and cystic fibrosis, the two parents who carry the recessive gene give rise to offspring in the ratio of 1:2:1, one expressing the disease, two not showing the symptoms but carrying the gene and one not carrying the gene for the disorder. Such conditions follow the Mendelian pattern of inheritance because the condition is caused by a mutation of a single gene. While the locating of the underlying gene in such situations is often difficult and time-consuming, the techniques of classical molecular genetic analysis, and linkage studies followed by positional cloning, are now well established. For monogenic diseases such as Huntington’s, a common pattern emerges in which a single gene, or small number of genes, that may harbour a number of rare mutations can be identified. Each mutation alone is then sufficient to produce a phenotype of the disease. Regarding bipolar disorder and schizophrenia, while there is some evidence that some families transmit the risk of the disease in a Mendelian fashion, the overall pattern of disease transmission is complex and it is unlikely that these conditions are due to a single gene. This suggests that there may be multiple genes involved, either many genes with strong alleles or common variants in many genes, each of which increases the risk of the disease in a modest way. An example of this would be Alzheimer’s disease, in which significant associations have been demonstrated between apolipoprotein (APO) E4 and the occurrence of the disease. An account of the genetic basis of Alzheimer’s disease can provide a useful example of the relationship between the genetic basis and the expression of the disease.Alzheimer’s disease exists in two major forms, the so-called early and late onset types. The former follows typical Mendelian inheritance while the latter shows a more complex, non-Mendelian, pattern of inheritance. The early onset form of the disease has permitted the identification of several genes which are causally related to the condition. In the elderly, in which Alzheimer’s disease has been estimated to occur in up to 20% of those aged 80 years, it has been shown that one allelic form of APO E is associated with an increased risk for developing the disease. Of the three APO E allelic forms in man, APO E4 is associated with the late onset form of the disease; this may account for up to 50% of the genetic risk for the late onset form whereas those carrying the less frequent E2 allele appear to be protected from the disease. In the early onset familial form of the disease, affecting approximately 5% of cases, there is a clear autosomal dominant pattern of inheritance. Mutations in three genes have been identified involving the beta amyloid precursor protein, presenilin-1 and presenilin-2. The function of these proteins is described in more detail in the chapter on the dementias . It has been estimated that mutations in these genes account for approximately 50% of the cases of the early onset disease.