Genetic Signatures of Exceptional Longevity in Humans

Paola Sebastiani1*, Nadia Solovieff1, Andrew T. DeWan2, Kyle M. Walsh2, Annibale Puca3, Stephen W. Hartley1, Efthymia Melista4, Stacy Andersen5, Daniel A. Dworkis6, Jemma B. Wilk7, Richard H. Myers7, Martin H. Steinberg6, Monty Montano6, Clinton T. Baldwin6,8, Josephine Hoh2, Thomas T. Perls5

1 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
2 Division of Chronic Disease Epidemiology, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America
3 IRCCS Multimedica, Milano, Italy; Istituto di Tecnologie Biomediche Consiglio Nazionale delle Ricerche, Segrate, Italy
4 Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts, United States of America
5 Section of Geriatrics, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston,
Massachusetts, United States of America
6 Department of Medicine, Boston University School of Medicine,
Boston,
Massachusetts,
United States of America
7 Department of Neurology,
Boston University School of Medicine,
Boston,
Massachusetts,
United States of America
8 Departments of Medicine and Pediatrics,
Boston University School of Medicine and Boston Medical Center,
Boston,
Massachusetts,
United States of America

Abstract

Like most complex phenotypes,
exceptional longevity is thought to reflect a combined influence of environmental (e.g.,
lifestyle choices,
where we live) and genetic factors.
To explore the genetic contribution,
we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls.
Using these data,
we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity,
and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years).
Consistent with the hypothesis that the genetic contribution is largest with the oldest ages,
the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death >102 and 85% to classify subjects with an age at death >105).
For further validation,
we applied the model to an additional,
unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity,
and 2863 unmatched controls with 61% specificity.
The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort.
Removal of this SNP from the model reduced the accuracy by only 1%.
Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different genetic signatures of varying predictive values for exceptional longevity.
The correlation between three signatures and three different life spans was replicated in the combined replication sets.
The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.

Citation:
Sebastiani P, Solovieff N, DeWan AT, Walsh KM, Puca A, et al. (2012)
Genetic Signatures of Exceptional Longevity in Humans.
PLoS ONE 7(1): doi:10.1371/journal.pone.0029848

Editor:
Greg Gibson, Georgia Institute of Technology, United States of America

Received November 21, 2011;
Accepted December 5, 2011;
Published January 18, 2012

Copyright:
2012 Sebastiani et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which allows unrestricted use,
distribution,
and reproduction in any medium,
provided the original author and source are credited.

Funding:
This work was supported by National Institutes of Health grants: R01 HL087681 (to MS),
K24 AG025727 (to TP),
R01 AR055115 (to MM),
RO1 (to CB),
R01 NS36711-09 (to RM).
In the study we included 254 subjects enrolled at ELIXIR.
The funders had no role in study design,
data collection and decision to publish,
or preparation of the manuscript.

Competing Interests:
In the study the authors included 254 subjects enrolled at ELIXIR.
There are no patentsexceptional longevity.posterior probability of average longevity). The trend shows that including more SNPs increases both sensitivity and specificity, but the gain in accuracy becomes less significant as SNPs with decreasing statistical significance are added. The sensitivity plateaus between 275-285 SNPs, suggesting that including more SNPs does not improve sensitivity further. Therefore, the search for predictive SNPs stopped at 281. A resampling approach was also used to validate this choice, and the effect of changing the SNP order in the heuristic search and possible lab-genotyping bias were examined.