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Informed GWAS Strategy Leads to Longevity-Linked Loci

NEW YORK (GenomeWeb) – With the help of information from past studies of human traits and diseases, a team from the US and Italy has identified five longevity-linked loci.

The researchers considered genotyping data for thousands of individuals enrolled in either the New England Centenarian Study (NECS) or the 90PLUS study, focused on individuals over the age of 100 or 90 years, respectively. Data from these individuals was assessed using an informed GWAS algorithm that accounted for each SNP's aggregate role in more than a dozen other traits and conditions, initially leading to eight extreme longevity-associated loci.

After replication testing in thousands more individuals, the team was left with four significant loci and a fifth locus showing more tenuous ties to old age. The results appeared online today in PLOS Genetics.

"Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits," senior author Stuart Kim, a genetics and developmental biology researcher at Stanford University, and his colleagues wrote.

"Beyond the study of human longevity," they added, "iGWAS can be applied to boost statistical power in any GWAS of a target phenotype by using larger GWAS of genetically related conditions."

In a longevity study published in PLOS One in 2012, members of another international team used data from the New England Centenarian study to find an association between longevity and a variant in the APOE gene. That variant, along with another 280 SNPs, made up a signature that successfully predicted longevity in other cohorts with some 60 to 85 percent accuracy.

For the current study, the researchers reasoned that variants involved in age-related traits or diseases might help in tracking down additional longevity-related sites in the genome.

To explore that possibility, they brought together data from 21 GWAS meta-analyses — on traits and diseases ranging from bone density or blood pressure to body mass index, heart disease, type 2 diabetes, and cancer — to search for disease or trait variants that overlapped with those found in the very elderly.

After demonstrating such overlap for nine of the conditions, the team narrowed in on SNPs contributing to 14 core conditions or traits for its iGWAS analyses, which involved assigning different weights to SNPs being evaluated for their potential roles in long life.

When they applied the iGWAS approach to genotyping data for 801 centenarians and 914 controls from NECS, as well as 5,406 over-90-year-olds and 15,112 controls from the 90PLUS study, the researchers saw eight extreme longevity-associated loci.

Associations at four of these sites in the genome remained significant following further testing on more centenarian cohorts: a group from Southern Italy that included 410 centenarians and 553 controls; 226 centenarians and 220 controls from Northern Italy; and a group of 474 centenarians and 799 controls of Ashkenazi Jewish descent.

The longevity-linked loci included a site near APOE/TOMM40 genes on chromosome 19, two chromosome 9 loci near CDKN2A/ANRIL and ABO, and a locus on chromosome 12 that was closest to SH2B3/ATXN2. Another locus that encompassed the HLA-DR region showed potential ties to longevity.

The results seem to make some functional sense, the researchers explained. Consistent with the association involving the ABO blood group gene, for example, the team noted that centenarians appear somewhat more likely to have the O blood group, which has been implicated as protective in past studies of heart disease and other conditions.

On the other hand, variants at the SH2B3/ATXN2 locus have been detected in studies of everything from heart disease, cholesterol levels, and blood pressure to rheumatoid arthritis and type 2 diabetes.