Variants thought to be behind inherited conditions prove difficult to pin down

By Tina Hesman Saey

Web edition: November 8, 2012

SAN FRANCISCO Rare tweaks in single letters of DNA are not as powerful a force in health and in common diseases as scientists hoped, new work suggests.

Common genetic variants contribute only a tiny bit to a persons risk of developing particular diseases, so researchers have turned to rare variants as a possible explanation for why some people inherit a propensity for heart disease, diabetes or other common ailments. These rare variants, present in a small percentage of people, are thought to affect how genes work. Two separate attempts to link rare variants with disease suggest that they may not affect disease risk more than common variants do.

We have learned that the effect size of these very rare variants is quite small, statistical geneticist Suzanne Leal of Baylor College of Medicine in Houston said November 6 during the annual meeting of the American Society of Human Genetics.

Leal and her colleagues have assembled excerpts of genetic instruction manuals, or genomes, for about 6,700 people of European or African American heritage. Instead of determining the makeup of the entire 3 billion letters of the peoples genetic instruction books, the team concentrated on just the highlights the tiny percentage of the genome that carries instructions for making proteins. Researchers call these genomic Cliffs notes exomes.

Genetic variants that introduce typos in this part of the genome may alter proteins molecules that carry out many important functions in cells and cause disease. Common variants dont often show up in protein-coding portions of genes, Leal and her colleagues discovered. Instead, the variants the scientists found tended to be carried by only a few people; some were so rare that only one person carried the variant.

Because each rare variant is found in so few people, it is difficult to do the sort of statistical tricks geneticists use to link common variants with disease incidence in populations. So Leal and her colleagues homed in on genes with an unusual burden of rare variants and studied whether they were associated with particular traits, including early heart attacks, high blood pressure and cholesterol levels.

Using this method, the team found that rare variants in a gene called APOC3 are associated with lower levels of triglycerides in the blood. High triglyceride levels have been linked to increased risk of cardiovascular disease, so people with the rare tweaks in APOC3 might be protected from heart attacks. However, the team doesnt know how big such an effect might be.

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Rare genetic tweaks may not be behind common diseases

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