High-Density Genomewide Linkage Analysis of Exceptional Human Longevity Identifies Multiple Novel

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/PrincipalFindings: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 on chromosome 3p24-22 with a genomewide significant allele-sharing LOD score of 4.02 (empirical P= 0.037) and a on chromosome 9q31-34 with a highly suggestive LOD score of 3.89 (empirical P= 0.054). The empirical P value for combined result was 0.002. A third novel locus with a LOD score of 4.05 on chromosome 12q24 was detected in a subset 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

107741) haplotypes [9–12]. Multiple recently reported associations between variants in FOXO3 (MIM 602681) and longevity are also quite promising [13–18]. Despite these important discoveries, additional alleles that may regulate aging in humans and allow a minority of the population to attain extreme old age have likely yet to be identified.

with age. These morbidities accompany an exponential increase in mortality rate that is maintained until approximately age 90, whereupon it starts to decelerate [1]. The reduction in observed versus expected mortality may be due to demographic selection, whereby individuals with alleles predisposing them to an early or average age of death, once deceased, leave behind a robust cohort depleted of detrimental alleles and/or enriched for alleles that promote longevity [2,3]. Centenarians often reach old age with delayed onset or absence of geriatric diseases [4], possibly benefitting from a ‘‘compression of morbidity’’ that confines these diseases to a short duration at the end of their life [5]. This correlation between exceptional longevity and healthy aging suggests that common genetic factors may underlie both traits. The epidemiology and phenotypes characteristic of human aging and results of candidate gene association studies have been reviewed elsewhere [6–8]. While many variants have demonstrat- ed preliminary evidence of association to exceptional longevity [7], the only confirmed associations are those of the APOE (MIM

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 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 genomewide 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

In addition to analyzing the complete Categories 1 to 10 (the ‘‘Total’’ group), we divided the sample set by two criteria into two subgroups for each. To explore differences between this study and the first scan [24], we analyzed (in Category 1) 129 of the 137 families used in the original cohort (the ‘‘Previous’’ subgroup) separately from 150 families recruited since that study was completed (the ‘‘New’’ subgroup). Because life expectancies show a gender bias, we also split the Total group into 140 sibships (in Category 1) with at least one male member (the male-containing, or ‘‘MC’’ subgroup) and 139 sibships comprised of only females (the female-only, or ‘‘FO’’ subgroup) (Table S1). Results that apply across all ten categories, in any group, are referred to as ‘‘Overall’’ for that group (for example, the Overall maximum LOD score).