From DNA Data to Disease Diagnosis

An interview with Dr. Eran Halperin, an expert in genetic research from the International Computer Science Institute in Berkeley, California, and Tel Aviv University.

What kind of information is used in association studies, and what answers can be obtained from them?

In a typical disease association study, a researcher collects DNA samples from a population of controls, or healthy individuals, and from a population of cases, who are individuals carrying the disease. The idea of such studies is that now we can search for differences in the DNA composition between the cases and the controls; such differences serve as an evidence for a relation between the disease and a genetic variant, which is a part of the DNA that varies across the population.

Due to the high cost of DNA sequencing, it is currently impossible to compare the entire DNA sequence across the set of individuals participating in the study; in a typical study there are thousands of cases and controls, and the cost of sequencing the entire genome of a single individual is still in the order of tens of thousands of dollars. For this reason, typically one will consider genetic variants that are common in the population. The most common variants are called Single Nucleotide Polymorphisms (SNPs), which are nucleotide base positions in the genome that differ across the population. Thus, if A,G,C, and T represent the four building blocks of the DNA, then for example in a SNP position you may find that 20% of the population carry the ‘A’ version and 80% carry the ‘C’ version. It is estimated that there are about 10 million SNPs in the genome, and in the other positions in the genome all individuals have the same DNA.

In a typical disease association study about 1 million SNPs are sampled per individual; we then search for differences between the frequencies of the SNPs in the cases and the controls. Once we discover such association we can further explore the reason for the association using ‘functional studies’ in which the specific genes are studied in the context of the disease. Furthermore, we can use the results of the genome-wide association studies to estimate the risk of an individual to develop a disease.

Where is this information obtained from? Are there specific, widely used processes for public and private researchers to obtain access to it?

The information is obtained in the lab, and is kept privately there, in order to protect the privacy of the study participants. In order to be able to share this information among scientists, there are databases maintained by the National Institute of Health in which the data is deposited and scientists can access the data if they need to use it for their research and if they prove that they can protect the privacy and rights of the study’s participants.

What is the strongest challenge currently being faced by researchers in genetics?

Genome-wide association studies have been very useful in discovering new genetic variants that are related to common diseases such breast cancer, Alzheimer’s disease, etc. However, there are studies that show that the heritability of these diseases is only very partially explained by the genetic variants that were found. For instance, it is believed that Crohn’s disease is more than 50% heritable, which means that out of all the factors triggering the disease, more than 50% are due to genetics, and the rest are due to environment. However, genome-wide association studies can only explain 10-15% out of those 50%, and the rest remains unexplained. Therefore, even though genome-wide association studies provided a leap in our understanding of the genetics of many diseases, they definitely do not provide the complete picture.

One of the major challenges set before us is how to fill this gap; there are a few plausible explanations that are currently being explored by scientists. For instance, one such explanation is that the disease is triggered by a combination of genes and environmental factors, and that the marginal effect of each of them is negligible. To find such combinations, larger association studies are currently being performed and advanced sequencing technologies are being utilized. Armed with these technologies, in the next few years geneticists are going to try to tackle this mystery of missing heritability by testing these and other hypotheses in different scenarios and for different common diseases.