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

1Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America, 2Division of Chronic Disease Epidemiology, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America, 3IRCCS Multimedica, Milano, Italy; Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche, Segrate, Italy, 4Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts, United States of America, 5Section of Geriatrics, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, United States of America, 6Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America, 7Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America, 8Departments 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 3 signatures and 3 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 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 patents, products in development or marketed to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Introduction

similarity of centenarians’ lifestyles to the general population [15], all argue that genetic factors play a much stronger role in living 25–35 years beyond the mid-eighties [10,16,17]. Impressively, siblings of centenarians born in 1900 have a relative risk of living nearly 100 years that is 8 (females) to 17 times (males) greater than that for the average of their birth cohort [10]. The rarity of the trait —only 1 centenarian amongst approximately 5,000 people in the US and only 1 supercentenarian (age 110+ years) amongst seven million people [18]— places exceptional longevity in a very different category from both average life expectancy and common complex traits associated with aging.

The average human lifespan in developed countries now ranges from about 80 to 85 years. Environmental factors such as lifestyle choices and where we choose to live as well as genetic factors all contribute to healthy aging. Supporting the importance of environmental factors in survival to old age is the 88 year average life expectancy of Seventh-Day Adventists [1], who by virtue of their religion have health related behaviors conducive to healthy aging.