The results, published in the Journals of Gerontology: Biological Sciences, highlight the importance of studying “truly rare survival, to discover combinations of common and rare variants associated with extreme longevity and longer health span,” the authors said.
The research group, led by Paola Sebastiani, professor of biostatistics the BU School of Public Health (BUSPH), created a consortium of four studies — the New England Centenarian Study, the Long Life Family Study, the Southern Italian Centenarian Study, and the Longevity Gene Project – to build a large sample of 2,070 people who survived to the oldest one percentile of survival for the 1900 birth year cohort. The researchers conducted various analyses to discover longevity-associated variants (LAVs), and to characterize those LAVs that differentiated survival to extreme age.
Their analysis identified new “extreme longevity-promoting variants” on chromosomes 4 and 7, while also confirming variants (SNPs, or single nucleotide polymorphisms) previously associated with longevity.
In addition, in two of the datasets where researchers had age-of-onset data for age-related diseases, they found that certain longevity alleles also were significantly associated with reduced risks for cardiovascular disease and hypertension.
“The data and survival analysis provide support for the hypothesis that the genetic makeup of extreme longevity is based on a combination of common and rare variants, with common variants that create the background to survive to relatively common old ages (e.g. into the 80s and 90s), and specific combinations of uncommon and rare variants that add an additional survival advantage to even older ages,” the authors wrote.
They said, however, that while the “yield of discovery” in the study was more substantial than in prior genome-wide association studies (GWAS) of extreme longevity, it remained disappointing, in that the two most significant genotypes discovered “are carried by a very small proportion of the cases included in the analysis,” meaning that much of the genetic variability around extreme lifespan remains unexplained.
“We expect that many more uncommon genetic variants remain to be discovered through sequencing of centenarian samples,” they wrote. “Larger sample sizes are needed to detect association of rare variants. . . and therefore promising associations that miss the threshold for genome-wide significance are important to discuss.”
BU co-authors on the study include: Stacy Andersen, assistant professor of medicine at BUSM and study manager of the New England Centenarian Study; Thomas Perls, professor of medicine and geriatrics at BUSM and principal investigator of the New England Centenarian Study; and Anastasia Gurinovich, of the BU Bioinformatics Program.
Funding: The study was supported by funding from the National Institute on Aging, the National Heart Lung Blood Institute, and the William Wood Foundation.
Source: Lisa Chedekel – Boston University Medical Center
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Original Research: Abstract for “Four Genome-Wide Association Studies Identify New Extreme Longevity Variants” by Paola Sebastiani, Anastasia Gurinovich, Harold Bae, Stacy Andersen, Alberto Malovini, Gil Atzmon, Francesco Villa, Aldi T. Kraja, Danny Ben-Avraham, Nir Barzilai, Annibale Puca, and Thomas T. Perls in Journals of Gerontology: Biological Sciences. Published online March 15 2017 doi:10.1093/gerona/glx027
Four Genome-Wide Association Studies Identify New Extreme Longevity Variants
The search for the genetic determinants of extreme human longevity has been challenged by the phenotype’s rarity and its nonspecific definition by investigators. To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort. We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years). The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer’s disease. The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.