A Genome-Wide Study Replicates Linkage of 3p22-24 to Extreme Longevity in Humans and Identifies Possible

Richard A. Kerber1,2*¤, Elizabeth O’Brien2¤, Kenneth M. Boucher1,2, Ken R. Smith2,4, Richard M.

1Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, United States of America, 2Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America, 3Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America, 4Department of Family and Consumer Studies, Salt Lake City, Utah, United States of America

Abstract

Methodology/PrincipalFindings:We identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related ‘‘affected individuals’’, defined as those in the top quartile for both excess longevity (EL =observed lifespan – expected lifespan) and familial excess longevity (FEL= weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak (Z=4.2, Monte Carlo-adjusted p-value 0.09) was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS) [1]. Meta-analysis of linkage scores on 3p from the two studies produced a minimum nominal p-value of 1.00561029 at 55 cM. Other potentially noteworthy peaks in our data occur on 18q23-24, 8q23, and 17q21. Meta-analysis results from combined UPDB and HMS data yielded additional support, but not formal replication, for linkage on 8q, 9q, and 17q.

Conclusions/Significance:Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region.

Citation: Kerber RA, O’Brien E, Boucher KM, Smith KR, Cawthon RM (2012) A Genome-Wide Study Replicates Linkage of 3p22-24 to Extreme Longevity in and Identifies Possible Additional Loci. PLoS ONE 7(4): e34746. doi:10.1371/journal.pone.0034746 Editor: Amanda Ewart Toland, Ohio State University Medical Center, United States of America Received July 1, 2011; Accepted March 9, 2012; Published April 10, 2012 Copyright:   2012 Kerber 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 research was supported by National Institutes of Health (NIH) grant R01-AG022095 (K. Smith, P.I.), NIH grant R21-AG030034 (R. Cawthon, P.I.), the Huntsman Cancer Foundation for database support provided to the Pedigree and Population Resource of the Huntsman Cancer Institute (HCI). Partial for all datasets within the UPDB was provided by the University of Utah, HCI and the HCI Cancer Center Support Grant, P30 CA42014 from the National Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: rich.kerber@louisville.edu

address: Department of Epidemiology and Population Health, University of Louisville, Louisville, Kentucky, United States of

Introduction

markers) in 2001 [13]. Later Boyden and Kunkel [1] produced an updated sib pair linkage analysis using an expanded dataset (632 subjects, consisting of some of the NECS subjects and additional subjects recruited more recently) along with a high-density panel of 10,000 single nucleotide polymorphism (SNP) markers.

It has long been thought that related individuals share a familial predisposition to longevity, and for more than a century numerous studies have investigated the degree to which human longevity might be an inherited characteristic [2–12]. Most studies of this type have reported small (,10%) to moderate (,30%) heritability of human longevity, amid differences in definitions of longevity, methods of measuring it, ascertaining individuals who demonstrate it, and in various behavioral and environmental settings. These methodological differences likely account for much of the variation in the resulting estimates of the heritability of longevity.

Lunetta and colleagues published a genome-wide association study (GWAS) of longevity among Framingham Study participants [14]. Despite numerous suggestive associations, Lunetta, et al. turned up no significant results based on their genome-wide SNP panel (of 100,000 markers). More recently, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium published a meta-analysis based on data from Framingham and three other cohort studies (the Age, Gene/ Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, and the Rotterdam Study); a confirmatory second stage genotyping included two additional datasets: the Leiden Longevity Study and the Danish 1905 cohort [15]. Combining

To date the most intensive genome-wide scans for markers associated with human longevity have been based on data collected by the New England Centenarian Study (NECS). Puca et al. first reported results of a sib-pair linkage study using a whole- genome scan (308 subjects genotyped with 400 microsatellite

pertaining to approximately 7 million individuals, many of whom are integrated into multigenerational pedigree networks 2 to 14 generations deep [22].