Human longevity and common variations in the LMNA gene: a meta-analysis

Karen N. Conneely,1 Brian C. Capell,2* Michael R. Erdos,2 Paola Sebastiani,3 Nadia Solovieff,3 Amy J. Swift,2 Clinton T. Baldwin,4 Temuri Budagov,5 Nir Barzilai,5 Gil Atzmon,5 Annibale A. Puca,6 Thomas T. Perls,4 Bard J. Geesaman,7

testing in the initial and follow-up samples (OR = 1.18, P = 7.5 · 10)4, multiple-testing-adjusted P = 0.037). These results suggest that LMNA variants may play a role in human lifespan. Key words: genetics; human; longevity; longevity gene.

Paola Sebastiani,

Nadia Solovieff,

Amy J. Swift,

Clinton T. Baldwin,

Temuri Budagov,

Nir Barzilai,

Gil Atzmon,

Annibale A. Puca,

Thomas T. Perls,

Bard J. Geesaman,

Michael Boehnke

and Francis S. Collins

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA

, USA

Genome Technology Branch, National Human Genome Research National Institutes of Health, Bethesda, MD

, USA

Department of Biostatistics, Boston University School of Public Health, Boston, MA

, USA

New England Centenarian Study, Geriatrics Section, Department of Medicine, Boston Medical Center and, Boston University School of Medicine, Boston, MA

, USA

Department of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY

, USA

Istituto Ricovero Cura Carattere Scientifico Multimedica, Milano, Italy Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche, Segrate, Italy

Elixir Pharmaceuticals, Cambridge, MA

, USA

Department of Biostatistics and Center for Statistical Genetics,

Introduction

Single gene mutations have been shown to extend the lifespan of worms, yeast, and mice (Kenyon, 2005). Similarly, twin studies have shown that 25–30% of the variance in human lifespan can be attributed to genetic differences (Herskind et al., 1996; Ljungquist et al., 1998; Skytthe et al., 2003). With the completion of the International HapMap Project, power to detect common variants for common and complex diseases has increased (Manolio et al., 2008), and the search for genetic contributors to human aging and lifespan has been accelerated. The results thus far have been somewhat discouraging: only APOE and FOXO3A have been consistently associated with longevity across populations in candidate gene studies (Christensen et al., 2006; Novelli et al., 2008). Even strong candidates such as the WRN gene associated with the premature aging syndrome, Werner syndrome (Castro et al., 2000), have displayed incon- sistent results (Christensen et al., 2006). Similarly, all longevity-associated SNPs reaching genome-wide significance in two recently published gen- ome-wide association studies were associated with the APOE gene (Dee- len et al., 2011; Nebel et al., 2011). However, because variants with subtler associations with longevity will not be detectable at genome-wide significance levels with conventional sample sizes, candidate gene studies remain a useful approach.

Summary

A mutation in the LMNA gene is responsible for the most dra- matic form of premature aging, Hutchinson–Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physi- ological cellular senescence. To explore further LMNA’s possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ‡ 95 years, N = 873) and geneti- cally matched younger controls (N = 443). We tested all common nonredundant haplotypes (frequency ‡ 0.05) based on sub- groups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR = 1.56, P = 2.5 · 10)5, multiple-testing-adjusted P = 0.0045). To attempt to replicate these results, we genotyped 3448 subjects from four indepen- dent samples of LLI and control subjects from (i) the New Eng- land Centenarian Study (NECS) (N = 738), (ii) the Southern Italian Centenarian Study (SICS) (N = 905), (iii) France (N = 1103), and (iv) the Einstein Ashkenazi Longevity Study (N = 702). We repli- cated the association with the most significant haplotype from our initial analysis in the NECS sample (OR = 1.60, P = 0.0023), but not in the other three samples (P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained signifi- cantly associated with longevity after adjustment for multiple

One major candidate gene for longevity that has not yet been explored is LMNA. Defects in the LMNA gene, which encodes the nuclear envelope proteins lamin A and lamin C, have been associated with at least 13 dis- eases, including Hutchinson–Gilford progeria syndrome (HGPS) (Gruen- baum et al., 2005; Capell & Collins, 2006). HGPS is a rare but devastating condition in which symptoms resembling premature aging appear at a very young age, typically within a year of birth. Owing to accelerated car- diovascular disease leading to eventual heart attack or stroke, individuals with HGPS have an average life expectancy of 13 years (Capell et al., 2007; Merideth et al., 2008).