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

Karen N. Conneely, Brian C. Capell, Michael R. Erdos, 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 inconsistent results (Christensen et al., 2006). Similarly, all longevity-associated SNPs reaching genome-wide significance in two recently published genome-wide association studies were associated with the APOE gene (Deelen 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 dramatic 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 physiological 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 genetically matched younger controls (N = 443). We tested all common nonredundant haplotypes (frequency > 0.05) based on subgroups 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 x 10^-5, multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3448 subjects from four independent samples of LLI and control subjects from (i) the New England 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 replicated 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 significantly associated with longevity after adjustment for multiple testing.