MoBio Genome-wide association study Chapter 10

Genome-wide association study (GWAS) is a method that identifies differences between individuals in single nucleotide polymorphisms (SNPs) that may be involved in causing diseases. The method is particularly suited to diseases that may be affected by one or many genetic changes throughout the genome. It is very difficult to identify the genes involved in such a disease using linkage analysis. The GWAS method relies on a genetic database that has been in development since 2002 called the International HapMap Project. The HapMap Project sequenced the genomes of several hundred individuals from around the world and identified groups of SNPs. The groups include SNPs that are located near to each other on chromosomes so they tend to stay together through recombination. The fact that the group stays together means that identifying one marker SNP is all that is needed to identify all the SNPs in the group. There are several million SNPs identified, but identifying them in other individuals who have not had their complete genome sequenced is much easier because only the marker SNPs need to be identified.

In a common design for a GWAS, two groups of individuals are chosen; one group has the disease, and the other group does not. The individuals in each group are matched in other characteristics to reduce the effect of confounding variables causing differences between the two groups. For example, the genotypes may differ because the two groups are mostly taken from different parts of the world. Once the individuals are chosen, and typically their numbers are a thousand or more for the study to work, samples of their DNA are obtained. The DNA is analyzed using automated systems to identify large differences in the percentage of particular SNPs between the two groups. Often the study examines a million or more SNPs in the DNA. The results of GWAS can be used in two ways: the genetic differences may be used as markers for susceptibility to the disease in undiagnosed individuals, and the particular genes identified can be targets for research into the molecular pathway of the disease and potential therapies. An offshoot of the discovery of gene associations with disease has been the formation of companies that provide so-called “personal genomics” that will identify risk levels for various diseases based on an individual’s SNP complement. The science behind these services is controversial.

Because GWAS looks for associations between genes and disease, these studies provide data for other research into causes, rather than answering specific questions themselves. An association between a gene difference and a disease does not necessarily mean there is a cause-and-effect relationship. However, some studies have provided useful information about the genetic causes of diseases. For example, three different studies in 2005 identified a gene for a protein involved in regulating inflammation in the body that is associated with a disease-causing blindness called age-related macular degeneration. This opened up new possibilities for research into the cause of this disease. A large number of genes have been identified to be associated with Crohn’s disease using GWAS, and some of these have suggested new hypothetical mechanisms for the cause of the disease.


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