The publication of a draft sequence of 90% of the human genome heralds an exciting era in human genetics research. In the past 20 years, efforts have focused on mapping and cloning the genes for about 1000 human genetic disorders. This has led to the development of comprehensive services for prenatal diagnosis, carrier testing, and presymptomatic testing of mendelian disorders such as cystic fibrosis and the muscular dystrophies. Although this progress has been important to families affected by these diseases, it has had a limited effect on public health. All this could change if knowledge of 2.9 gigabases of the human genome sequence allows us to identify susceptibility genes for common diseases such as diabetes, asthma, and cancer. It may also lead to the identification of genetic variants that define a patient's response to a particular drug. If the promise of the genome sequence is even partially fulfilled, the next decade will see genetics spreading rapidly beyond the confines of specialist centres to impact on the diagnosis and management of common disorders in primary care.
Our risk of contracting common diseases is generally thought to be determined largely by environment and lifestyle. However, there is strong epidemiological evidence that genes contribute to overall risk. In multiple sclerosis, for example, the siblings of an affected person have a 25-fold increase in risk of developing the disease compared with the general population. Since relatives often share a common environment, the inheritability of a disease can also be assessed by comparing concordance rates for a disease in monozygotic and dizygotic twins. A higher concordance in monozygotic twins than dizygotic twins would suggest that the risk is determined mainly by genes. In multiple sclerosis, concordance is 30% for monozygotic twins and 3% for dizygotic twins, which shows that genes are important but that there is also a substantial environmental component.
Multiple sclerosis is an example of a complex disorder in which both genes and environment contribute to pathogenesis. There is also evidence that multiple genes contribute to disease susceptibility, each of which may confer a small increase in risk (perhaps up to fivefold). These conditions are also therefore referred to as polygenic disorders, and the susceptibility genes are called complex disease genes.
Mathew C., BMJ 2001;322:1031-1034 ( 28 April )
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Submission date: 04/05/01