GWAS and Differences in DNA Between Tissues

Posted by Bob Grant
[Entry posted at 20th July 2009 04:52 PM GMT]
http://www.the-scientist.com/blog
Recent findings may spell trouble for genome-wide association studies based on DNA obtained through blood samples: Genetic material may vary between blood cells and other tissues in a single individual, a study in the July issue of Human Mutation reports.

Image: Wikimedia

The study “raises a very interesting question,” Howard Edenberg, director of the Indiana University School of Medicine’s center for medical genomics, told The Scientist. Many genome-wide association studies — especially studies on systemic diseases such as diabetes and atherosclerosis — depend solely upon DNA harvested from blood samples to identify genes associated with medical conditions. But this study “suggests that looking only at blood, you may miss some things.”

Searching for the genes behind a fatal condition called abdominal aortic aneurysm (AAA), researchers from McGill University in Montreal found that complementary DNA from diseased abdominal aortic tissue did not match genomic DNA from leukocytes in blood from the same patient. “We did not expect to find a difference in the tissue [genes] compared to the leukocyte [genes],” said endocrinologist Morris Schweitzer, who led the study.

Schweitzer and his team uncovered three single nucleotide polymorphisms (SNPs) in samples of diseased tissue from 31 AAA patients that were not present in matching blood samples. They also tested five aortic and blood samples from normal individuals and found the same discrepancy. Schweitzer said that the apparent genetic difference between different cells in the body may cast some doubt on genome-wide association studies that only use DNA from blood samples to infer disease states. “I think they may not be accurate because they might not reflect what’s in the tissue,” he said, adding that researchers should look upon such genetic results “very carefully and very trepidatiously”

Edenberg, who was not involved with the study but who conducts genome-wide association studies to explore the genetic roots of alcoholism and bipolar disorder, said that while the findings are interesting, they are very preliminary. “If they’re correct about this, and there are these genomic differences between tissues and blood at certain alleles, then we’re missing some things,” he said. Edenberg explained that experimenters generally take into account that such studies are somewhat “underpowered” in terms of their ability to catch every genetic indicator of disease. Schweitzer’s results, he noted, may add another layer to this consideration, but do not suggest that genome-wide association studies would turn up false positives, or blood-based genes mistakenly attributed to a particular disease.

Sudha Seshadri, a Boston University neurologist who was not involved in the study, told The Scientist that though the McGill group’s results are important, they do not negate genome-wide association data that scientists have already gathered. “I don’t think [the study] says much about the usefulness or validity of genome-wide association studies as they are being done in cohorts around the world.” Genome-wide studies on diabetes, for example, have identified about 16 genes that are related (in varying degrees) to the disease, said Seshadri, who collaborates on the Framingham Heart Study, a six-decade longitudinal study on more than 5,000 people that has more recently included genomic data.

“I think I would have suggested a few more experiments, personally,” Edenberg added. In particular, he pointed to the fact that the McGill researchers were comparing complementary DNA from aortic tissue to genomic DNA from blood. “At the moment,” he said, the discrepancy “seems relatively compatible with RNA editing [rather] than with a genomic issue.” The study should have compared genomic DNA from the aortic tissues with the genomic blood DNA, and cDNA from both cell types, Edenberg said.

Schweitzer said his group is currently working on this experiment and “should have results probably in a couple of weeks.” He noted that differences between tissue and blood DNA may account for the relatively low levels of association turned up by most genome-wide association studies. Of all the genome-wide association studies that have been conducted, he said, “No one has really found that one miracle gene that really points to something.”

Seshadri, however, said it’s hasty to dismiss the value of such studies. “I think [the authors] make some provocative statements that express a viewpoint, but not a widely-accepted viewpoint,” she said. “It’s far too early in the process of genome-wide association studies to conclude that they have not been fruitful.”

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