Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Marian Beekmana, Christa Nederstigt, H. Eka D. Suchimana, Dennis Kremer, Ruud van der Breggen, Nico Lakenberga, Wendimagegn Ghidey Alemayehub, Anton J. M. de Craenc, Rudi G. J. Westendorpc, Dorret I. Boomsmad, Eco J. C. de Geusd, Jeanine J. Houwing-Duistermaatb, Bastiaan T. Heijmansa, and P. Eline Slagbooma,e.

a Molecular Epidemiology, b Medical Statistics and Bioinformatics, and c Gerontology and Geriatrics at Leiden University Medical Center in Leiden, The Netherlands; d Biological Psychology at Vrije Universiteit Amsterdam in Amsterdam, The Netherlands; and e Netherlands Consortium for Healthy Ageing.

Edited* by Charles R. Cantor from Sequenom Inc., San Diego, CA. Approved on September 9th, 2010 (received for review on March 17th, 2010).

A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 years of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease.

In a meta-analysis of the two cohorts, nominal significant associations with survival into old age were observed for seven individual SNPs (0.023 < P < 0.046; Table S5), but none was significant when accounting for multiple testing (P < 0.001).

The offspring of long-lived families have a lifelong survival advantage that can be attributed to a lower risk for coronary artery disease, cancer, and type 2 diabetes. These observations may be explained by the presence of alleles protecting against diseases that contribute to population mortality or the absence of alleles promoting such diseases. The latter hypothesis can be tested now that genome-wide association studies (GWASs) have produced a series of SNPs showing robust associations with common diseases that are the main causes of death.

The effect on fatal disease can also be analyzed by a cross-sectional comparison of healthy groups of different age categories. Because disease risk alleles contribute to morbidity and mortality, the frequencies of those risk alleles are expected to decrease in the healthy elderly individuals of the population at large. However, the frequency of deleterious genotypes might increase among long-lived individuals because their protective genotype allows disease-related genes to accumulate. To investigate the presence of such a buffering mechanism, we divided all subjects and controls (n = 3,590) into 10 age groups (Table S6) and determined the mean number of risk alleles and the allele frequencies of the 30 SNPs in each age group. We did not observe differences in the mean number of risk alleles (Fig. S1) or in SNP-specific allele frequencies (Dataset S1).

We tested whether nonagenarians from the Leiden Longevity Study (LLS) and octogenarians from the Leiden 85 Plus Study carried lower total numbers of 30 major GWAS-identified disease susceptibility alleles than younger controls.

Reviewing the catalog of published GWASs for coronary artery disease, heart failure, cancer, and type 2 diabetes up to February 2009 revealed 30 SNPs in 22 disease-associated loci (Table S1). These SNPs were investigated for their deleterious role in survival beyond 85 years of age by comparing 723 nonagenarian siblings (mean age of 94 years) from the LLS, representing familial long-lived cases, and 721 unrelated younger controls (mean age of 52 years). We also compared 979 singleton long-lived individuals older than 85 years (mean age of 87 years) of age from the population-based Leiden 85 Plus Study and 1,167 younger controls (mean age of 41 years) from the Netherlands Twin Register.

A lower genetic predisposition for disease in long-lived individuals may explain why long-lived families have a delayed age of onset and lower mortality attributable to common age-related diseases. Therefore, our aim was to investigate whether the absence of currently known genetic susceptibility alleles is essential for survival into old age. Hence, we compared the cumulative effect of alleles that have convincingly been identified as risk factors for cardiovascular disease, type 2 diabetes, and cancer between long-lived individuals (aged 85 years and older) and the middle-aged general population, in whom the disease risk alleles are generally discovered.

Despite the fact that cardiovascular disease, cancer, and type 2 diabetesNine additional disease-associated SNPs were selected, which were in low to moderate linkage disequilibrium (r2 < 0.80) with the most replicated SNP. Consequently, 32 SNPs were chosen for genotyping using the Sequenom iPLEX. However, two of the SNPs failed during genotyping, reducing the number of SNPs studied to 30, which covered 22 loci. One locus was represented by four SNPs (9p21.3), one by three SNPs (8q24.21), and three loci were represented by two SNPs each. Seventeen loci were represented by one SNP. Our study found no significant odds for carriers with the highest number of risk alleles to survive into old age, with an OR of 0.99 (95% CI: 0.97-1.03). The boundaries of the 95% CI in this analysis are close to unity, which was also the case for the boundaries of the OR per extra risk allele. Although it remains to be investigated whether disease risk alleles are associated with longevity, our data suggest that longevity is not likely to be determined by the absence of GWAS-identified risk alleles for cardiovascular disease, cancer, and type 2 diabetes, accounting for their interaction with environmental factors.