Genetic Mapping Techniques Used By The Johns Hopkins Epidemiology-Genetic Program in Psychiatry

        The goal is to determine the genetic components of schizophrenia and bipolar disorder. To reach this goal, the study team is utilizing several genetic mapping techniques to determine the location of risk genes. This is no small job- we each have about 100,000 genes, and trying to locate the small number of risk genes is like looking for the proverbial needle in the haystack! Luckily, scientists have developed laboratory techniques that can help us in our search.

Before reviewing the mapping techniques, it is important to review the most important aspects of genetics.

• Genes hold all of our hereditary information, and provide the "genetic code" that allows our bodies to develop, grow, and function. Genes can play a role in our risk to develop certain disorders. Our environment affects how our genes function.
• Genes are made up of DNA (Deoxyribonucleic Acid.) DNA is the genetic alphabet.
• We inherit half of our genetic information from our mother, and half from our father.
• Our genes are packaged in structures called chromosomes. Genes lined up on chromosomes can be thought of like beads lined up on a string. Humans have 23 pairs of chromosomes in almost every cell of their body.

Following is a brief description of the two major mapping techniques that we are using, linkage studies and association studies.

Linkage is a method that allows us to determine regions of chromosomes that are likely to contain a risk gene, and rule out areas where there is a low chance of finding a risk gene. Linkage works by using markers, which are well-characterized regions of DNA. Many markers have been identified by the Human Genome Project, and by other studies to map chromosome regions.

In linkage studies, researchers are searching for a marker that is consistently present in those with a condition, and is not present in those without the condition. When we find a marker that is found with the presence of a condition, the marker and the disease-causing gene are said to be linked, and are assumed to be very close together. By looking at large numbers of families, researchers can be very confident that there is a risk gene somewhere close to the marker.

In our studies, we have looked at hundreds of markers to help narrow down the chromosome regions where risk genes may lie. We have strong evidence that there are risk genes for schizophrenia on chromosome 22 (22q11), chromosome 13 (13q32) and chromosome 8 (8p21.) It is possible that there are also risk genes for bipolar disorder on chromosomes 22 and 13. We are continuing to use linkage to locate possible risk genes for both disorders.

There are several downsides to using linkage. First, it requires the use of DNA from both affected and unaffected individuals from the same family. Second, linkage requires the use of DNA from lots of families. Lastly, linkage is a very time and labor intensive method.

Analogy for linkage: Our genetic information is like a large phone book. In that phone book, we are interested in locating a person named Bob. We do not know Bob’s last name, or Bob’s address. Linkage allows us to take that whole phone book, and narrow our search down to a couple of pages of names. We still have not located Bob, but we are getting closer!

After using linkage to get an idea where risk genes may be located, we use association to try to locate the risk gene. Association allows us to test candidate genes, or very small genetic regions, to see if they are associated with having the condition. These tests can result in the location of a risk gene.

Association studies also require the use of DNA from many individuals. However, association studies do not use families. Rather, they look at DNA from affected individuals compared to DNA of controls (non-affected individuals who do not have to be relatives.)

Our research group is just beginning to use association methods. We hope that association studies will help us pinpoint specific risk genes for bipolar disorder and schizophrenia.

Analogy for association studies: Thanks to linkage, we have narrowed our phone book down to a couple of pages. However, we still have not located Bob. Association allows us to start calling all of the phone numbers on those pages, until one of the numbers happens to be Bob!

The following resources can provide more information on genetics and genetic mapping techniques:

National Human Genome Research Institute Glossary of Genetic Terms
http://www.nhgri.nih.gov/DIR/VIP/Glossary/

Department of Energy Primer on Molecular Genetics
http://www.bis.med.jhmi.edu/Dan/DOE/intro.html