Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Refined tools help pinpoint disease-causing genes

30.04.2010
New approach also specifies results for individual patients

In findings that may speed the search for disease-causing genes, a new study challenges the prevailing view that common diseases are usually caused by common gene variants (mutations). Instead, say genetics researchers, the culprits may be numerous rare variants, located in DNA sequences farther away from the original "hot spots" than scientists have been accustomed to look.

Using an approach that detects rare but powerful causal gene variants, the researchers say they have accounted for a significant proportion of the "missing heritability" problem – the disappointing fact that, to date, conventional gene-hunting studies have often failed to identify, when searching for gene variants, variants that cause a large proportion of common diseases, such as heart disease, cancers and diabetes.

The new approach draws on existing data from genome-wise association studies (GWAS) that have already been performed, reanalyzing the data to pinpoint causal variants that have not been identified previously.

Furthermore, the technique may allow researchers to identify individuals whose DNA is more likely to carry specific mutations in the causal genes. "Our approach draws us closer to the goal of personalized medicine, in which treatment will be tailored to an individual's genetic profile," said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia. "When we can say that a specific gene mutation causes a patient's disease, we have more meaningful diagnostic results. Identifying causal variants in disease genes provides an opportunity to develop drugs to rectify the biological consequences of these mutated genes."

Hakonarson and colleagues, including first author Kai Wang, Ph.D., of Children's Hospital, collaborated with David B. Goldstein, Ph.D., director of the Center for Human Genome Variation at Duke University. The study appears online today in The American Journal of Human Genetics.

Earlier this year, Goldstein led a study, in collaboration with Hakonarson and Wang, that presented a model of this approach, performing computer simulations based on GWAS data. The current study strengthens the model by analyzing real DNA sequencing data from two well-known diseases—Crohn disease and genetic hearing loss.

A GWAS uses gene chips in automated systems that analyze about 500,000 to one million sites where single-letter differences in DNA tend to occur; these differences are called single-nucleotide polymorphisms, or SNPs. In using these SNP chips over the past decade in comparing DNA samples between healthy subjects and patients, scientists have identified thousands of SNPs that associate with common complex diseases. However, geneticists believe that the SNPs investigated by the gene chips do not themselves cause a disease, but instead serve as a "tag," a marker linked to the actual causal mutations that may reside in a nearby region.

After a GWAS finds SNPs linked to a disease, researchers then perform a "fine-mapping" study by additional genotyping--sequencing of the gene regions near the SNP signal, to uncover an altered gene that harbors a mutation responsible for the disease. Most of the results, said Hakonarson, have been unimpressive, yielding causal variants with very small effects. "These efforts have not identified 'smoking gun' mutations that cause a disease," he added.

The current study uses different assumptions. Instead of inferring the presence of a nearby common disease-causing gene linked to a given SNP, the researchers propose that numerous rare causal variants may separately "hitchhike" on the same tag SNP, often from locations further away than those scrutinized in conventional fine-mapping approaches. Those more distant genetic factors are typically overlooked in the conventional GWAS approach. By missing these actual causative gene variants, the conventional technique underestimates the strength of their effect on the disease.

By applying their methods to real DNA samples from patients with genetic hearing loss, the researchers' approach helped them to select from GWAS data a subset of cases for sequencing analysis that were most likely to carry causative mutations. Sequencing the DNA in this subset, the study team found that the majority of those patients carried an actual mutation known to cause hearing loss. "Our technique suggests that when we do our resequencing follow-up studies, we can identify people who are much more likely to carry a causative gene," said Kai Wang, who analyzed the dataset. Hakonarson added, "We present a more efficient approach for mining GWAS data to find the actual causative gene variants that will have future utility in designing therapies."

The National Institutes of Health provided funding support for this study, along with an Institutional Development Award from The Children's Hospital of Philadelphia. Co-authors with Hakonarson, Goldstein and Wang were Samuel P. Dickson, Ph.D., of Duke University; and Catherine A. Stolle, Ph.D., and Ian D. Krantz, M.D., of The Children's Hospital of Philadelphia.

"Interpretation of Association Signals and Identification of Causal Variants from Genome-Wide Association Studies," The American Journal of Human Genetics, published online April 29, 2010. http://dx.doi.org/10.1016/j.ajhg.2010.04.003

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 460-bed hospital recognition as a leading advocate for children and adolescents.

John Ascenzi | EurekAlert!
Further information:
http://www.chop.edu

More articles from Life Sciences:

nachricht New technique unveils 'matrix' inside tissues and tumors
29.06.2017 | University of Copenhagen The Faculty of Health and Medical Sciences

nachricht Designed proteins to treat muscular dystrophy
29.06.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making Waves

Computer scientists use wave packet theory to develop realistic, detailed water wave simulations in real time. Their results will be presented at this year’s SIGGRAPH conference.

Think about the last time you were at a lake, river, or the ocean. Remember the ripples of the water, the waves crashing against the rocks, the wake following...

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Nanostructures taste the rainbow

29.06.2017 | Physics and Astronomy

New technique unveils 'matrix' inside tissues and tumors

29.06.2017 | Life Sciences

Cystic fibrosis alters the structure of mucus in airways

29.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>