Genetic clues could provide advance warning of brain aneurysm rupture.

A three-dimensional CT scan shows a bulging aneurysm (red) in the brain.

A ruptured brain aneurysm can kill with the speed and surprise of an assassin's bullet: before rupture, most intact brain aneurysms—distended areas in blood vessel walls—do not cause symptoms. A lucky patient will have an intense headache before the aneurysm bursts; this warning can alert doctors to check for an aneurysm using a brain scan so that they can correct the problem surgically. Now, an international study has found three genetic clues to help anticipate and prevent brain aneurysm rupture.

HHMI investigator Richard P. Lifton and Murat Gunel, of the Yale School of Medicine, led an international team in the first genomewide search for common genetic markers for brain aneurysms. They uncovered three genetic variations that together can increase the risk of the condition threefold—by about the same amount as known nongenetic factors such as high blood pressure, smoking, and age. The results were published in the December 2008 issue of Nature Genetics.

The study compared the genomes of more than 10,000 people—2,100 with intact or ruptured brain aneurysms and 8,000 controls. Specifically, the scientists examined over 300,000 single nucleotide polymorphisms (SNPs)—areas in the genome known to vary in the human population. They were looking for any SNPs more commonly found in individuals with aneurysms.

The subjects were Finnish, Dutch, and Japanese. These countries' populations are relatively genetically homogeneous, which helped the researchers distinguish only the relevant genetic patterns.

The three genetic markers the scientists found will increase understanding of the biological causes of brain aneurysms and help doctors to identify people at risk. Two variants lie near genes that function in the formation and maintenance of blood vessels. The third, which had previously been linked to brain aneurysms, lies near a gene associated with arterial diseases.

“We ought to be able to identify more variants that contribute as we study more patients,” Lifton says. Both lifestyle and genetic factors would then help doctors identify individuals who should receive regular brain scans.

Photo: CHU Poitiers / Photo Researchers, Inc.