High-Density Genome-Wide Linkage Analysis of Exceptional Human Longevity Identifies Multiple Novel Loci

Steven E. Boyden1,2, Louis M.

1Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America, 2Program in Genomics, Division of Genetics, and The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts, United States of America, 3Howard Hughes Medical Institute, Children's Hospital Boston, Boston, Massachusetts, United States of America

Abstract

Background: Human lifespan is approximately 25% heritable, and genetic factors may be particularly important for achieving exceptional longevity. Accordingly, siblings of centenarians have a dramatically higher probability of reaching extreme old age than the general population.

Methodology/Principal Findings: To map the loci conferring a survival advantage, we performed the second linkage scan on human longevity and the first using a high-density marker panel of single nucleotide polymorphisms. Systematically testing a range of minimum age cutoffs in 279 families with multiple long-lived siblings, we identified a locus on chromosome 3p24-22 with a genome-wide significant allele-sharing LOD score of 4.02 (empirical P= 0.037) and a locus on chromosome 9q31-34 with a highly suggestive LOD score of 3.89 (empirical P= 0.054). The empirical P value for the combined result was 0.002. A third novel locus with a LOD score of 4.05 on chromosome 12q24 was detected in a subset of the data, and we also obtained modest evidence for a previously reported interval on chromosome 4q22-25.

Conclusions/Significance: Our linkage data should facilitate the discovery of both common and rare variants that determine genetic variability in lifespan.

Funding: This work was supported by the Howard Hughes Medical Institute. Microarray genotyping experiments were performed using equipment in the Microarray Core Facility of the Molecular Genetics Core Facility at Children's Hospital Boston, supported by NIH-P30-HD18655 through the Intellectual and Developmental Disabilities Research Center and NIH-P50-NS40828 through the Neuromuscular Disease Project. LMK is an investigator with the Howard Hughes Medical 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: kunkel@enders.tch.harvard.edu

Introduction

Estimates of the heritability of normal human lifespan range from 10% to 58%, averaging about 25% [19]. The genetic contribution to lifespan grows markedly after age 60, indicating that the heritability of exceptional longevity may be substantially higher than these estimates [20]. The relative survival probability for siblings of centenarians increases steadily with age until male and female siblings have a 17-fold and 8-fold increased chance, respectively, of reaching age 100 compared to others from their birth cohort [21]. Moreover, while natural lifespan is likely a complex trait controlled by many genes with small effect sizes, extreme longevity may be determined by fewer genes of stronger effect [22,23] and may therefore be amenable to linkage analysis.

The only previous genome-wide scan for linkage to longevity was conducted in part by a member of our group (LMK) and identified a region on chromosome 4q22-25 as significantly linked in 137 sibships of centenarians and nonagenarians [24]. A subsequent genome-wide scan for healthy aging in a smaller and younger cohort provided weak support for the chromosome 4q22-25 linkage [25], whereas a targeted study of 164 sibships of nonagenarians did not find linkage to the locus [26], nor did a genome-wide scan on bone characteristics as a biomarker for biological aging [27]. All these studies used microsatellite markers with 510 cM spacing. To assess the linkage to chromosome 4 and identify new loci, we performed the most powerful linkage scan to date on exceptional longevity. Though the evidence for linkage to chromosome 4 remains equivocal, several novel loci were discovered in our scan, including a region on chromosome 3p24-22 with an empirically genome-wide significant LOD score of 4.02 and a region on chromosome 9q31-34 with a LOD score of 3.89.

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