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GWAS IDs Variants For Predicting Exceptional Longevity in Humans

By Andrea Anderson

NEW YORK (GenomeWeb News) – Exceptional longevity in humans is linked to survival-associated genetic patterns rather than a dearth of disease-associated variants, according to the authors of a genome-wide association study appearing in the early, online version of Science today.

A Boston University-led research team did a GWAS involving more than 1,000 individuals over the age of 100 years old and about as many control individuals, identifying a set of SNPs that appears to be useful for predicting human longevity and finding genetic sub-groups within the centenarian population.

"We think these analyses represent an important step forward in our understanding of the genetics of exceptional longevity as well as the aging," lead author Paola Sebastiani, a biostatistics researcher at Boston University's School of Public Health, said during a telephone briefing with reporters this week.

Although environmental factors such as diet and exercise are thought to influence lifespan to a greater extent than genetics, the researchers explained, studies suggest extremely long life, or "exceptional longevity," does run in families.

"We have noted and others have noted as well that there's a very strong familial component to exceptional longevity," senior author Thomas Perls, a geriatrics researcher at Boston University and director of the New England Centenarian Study (NECS), told reporters. "That, in conjunction with some other work, has made us believe that genetics is playing a very important role in this wonderful trait."

To explore this genetic component of aging, the researchers focused on centenarians, individuals over the age of 100 years old, and super-centenarians, individuals who are at least 110 years old. Centenarians are of interest to researchers because they not only have long lifespans, but also tend to age well, Perls noted.

"90 percent of centenarians are disability-free at the average age of 93," he said. "They very much compress their diseases or disability to the very end of their lives."

For the current study, researchers assessed roughly 295,000 SNPs in 801 individuals between the ages of 95 and 119 years old from the NECS and compared the SNP patterns in this group with those for 926 genetically matched controls who were either recruited through NECS or selected from an Illumina control database.

Of the 70 SNPs with genome-wide significance in this discovery set, the team replicated their findings for 33 of the SNPs when they tested 254 more 90- to 114-year-olds enrolled in a study by Elixir Pharmaceuticals as well as 341 control individuals from the Illumina database.

The researchers also repeated their GWAS in 867 individuals enrolled through a Parkinson's disease study, again verifying the associations. From the dozens of SNPs identified, just five had turned up in previous GWAS for common diseases.

From there, the team plugged their newly identified SNPs into a computational model for finding additional longevity-associated variants, pinpointing a set of 150 predictive SNPs.

When they used this SNP set to test an independent group of centenarians, the researchers found that they could predict long life with 77 percent accuracy.

While that level of accuracy points to a strong genetic component to exceptional longevity, Sebastiani explained, the 23 percent error rate might be due to either the presence of yet undetected genetic variants or variable environmental or lifestyle factors.

"Genetics are fundamental in exceptional longevity, but it's not the only thing," she said.

And not every centenarian had the same genetic patterns. On the contrary, the team found that they could classify almost all of the centenarians in their discovery set into 19 sub-groups, each containing at least eight individuals who shared different genetic signatures.

"These signatures represent the different genetic paths to age 100 and plus," Sebastiani said, "and shed light on the genetics of healthy aging."

Some of these signatures correlated with longest overall survival, for instance, while others were linked to a delayed onset of age-related diseases such as dementia, cardiovascular disease, or hypertensions.

Unexpectedly though, when the team compared the prevalence of known disease risk variants in centenarians and controls, they did not find significant differences, leading them to speculate that the most aged individuals might carry additional protective variants that offset inherent disease risk.

"What makes these people live a very long life is not a lack of genetic predisposition to diseases, but rather enrichment of longevity-associated variants that may be protective and may even cancel the genetic effects of disease-associated variants," Sebastiani said.

Based on such findings, the researchers urged caution in interpreting disease risk based on known disease-associated variants alone.

"If you want to calculate the risk for a disease based on disease-associated variants," Sebastiani explained, "your calculation may be incomplete if the overall genetic background is ignored."

The team is planning follow-up studies, including research with collaborators in Japan looking at longevity-related genetic patterns in individuals from that country.

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