30.3: Goals of investigating the genetic basis of disease

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Having established that there is a genetic component to disease traits, how can this research help meet outstanding medical challenges? There are two main ways:

Personalized genomic medicine

Variants can be used in genetic screens to test for increased risk for the disease trait and provide individualized medical insights. A large number of companies are now providing personalized genomic services through screening for cancer recurrence risk, genetic disorders (including prenatal screening), and common disease. Individualized genomic medicine can help identify likelihood to benefit from specific therapeutic interventions, or can predict adverse drug responses.

Informing therapeutic development

Identifying genetic variants which explain the disease trait contributes to our ability to understand the mechanism (the biochemical pathways, etc.) by which the disease manifests. This allows us to engineer drugs that are more effective at targeting the causal pathways in disease. This is of particular interest

Figure 30.1: Examples of diseases and quantitative traits which have genetic components

Figure 30.2: The drug development process

because our current drug development process makes it difficult to develop drugs for certain disorders. For example, in the last 50 years, no truly novel compounds have been developed to treat various psychiatric disorders such as schizophrenia. The identification of genetically associated genes can help identify targets to start drug development.

Figure 30.2 depicts the cycle of drug development. The drug development process starts with hypothesizing a possible target of interest that might be related to a disease. After biochemical evaluations and drug development, the target is tested in model organisms. If the drug is effective in model organisms, it is tested in humans through clinical trials. However, the vast majority of drugs which make it through this process end up being ineffective in treating the disease for which they were originally designed. This result is mainly a consequence of faulty target selection as the basis of the disease in question. Statins are a prominent example of highly effective drugs developed after work on understanding the genetic basis of the disease trait they are targeted at. Dr. Michael Brown and Dr. Joseph Goldstein won the Nobel Prize in Physiology or Medicine in 1985 for their work on the regulation of LDL cholesterol metabolism [5]. They were able to isolate the cause of extreme familial hypercholesterolemia (FH), a Mendelian disorder, to mutations of a single gene encoding an LDL receptor. Moreover, they were able to identify the biochemical pathway which was affected by the mutation to create the disease condition. Statins target that pathway, making them useful not only to individuals suffering from FH, but also as an effective treatment for high LDL cholesterol in the general population.