Rare genetic tweaks may not be behind common diseases

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

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 person’s 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 people’s 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 Cliff’s 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 don’t 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 doesn’t know how big such an effect might be.

In fact, it’s still unclear how much an individual’s particular rare variant contributes to the risk of developing a disease at all; the variants investigated in this study were just too rare make the determination by statistical methods, Leal said. More research will be needed to figure out just what each individual variant does and how it may interact with all the other genetic variants a person carries.

Other scientists may soon be able to help reveal more about the biological effects of some rare variants. Erica Davis of Duke University and colleagues tested rare variants found in exomes of 15 children who had inherited diseases or developmental abnormalities with unknown causes. Each of the children had up to five new variants not found in their parents, but the researchers could not tell which, if any, of those variants caused the kids’ symptoms. To find out, the team made zebra fish embryos that carried genes with the same variants found in the children. If the fish developed the same characteristics the children had, the researchers would be able to tell that the particular variant probably caused the problem. Only 17 percent of the variants were clearly harmful, Davis said at the genetics meeting. The remaining 83 percent of variants were “uninterpretable,” she said. “We don’t know if they are pathogenic or not.”

Although zebra fish are useful for testing the effect of genetic variants early in development, they may not be as good for finding variants that produce defects later in development, says Harry Ostrer, a geneticist at Albert Einstein College of Medicine in New York City.

It is probably too early to say to what extent rare variants contribute to common diseases, he says. These two studies considered only variants in protein-producing parts of the genome, but variants in parts of the genome that regulate when, where and how active genes are may also be important.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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