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

Richard A. Kerber1,2*, Elizabeth O'Brien2, Kenneth M. Boucher1,2, Ken R. Smith2,4, Richard M. Cawthon3

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

Abstract

Methodology/Principal Findings:
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 allows 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 funding 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 America

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.