Genome-wide association study (GWAS)-identi ed disease risk alleles do not compromise human longevity

Marian Beekmana,1, Christa Nederstigta, H. Eka D. Suchimana, Dennis Kremera, Ruud van der Breggena, 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

aMolecular Epidemiology, bMedical Statistics and Bioinformatics, and cGerontology and Geriatrics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; dBiological Psychology, Vrije Universiteit Amsterdam, 1081 BT, Amsterdam, The Netherlands; and eNetherlands Consortium for Healthy 2300 RC, Leiden, The Netherlands

Edited* by Charles R. Cantor, Sequenom, Inc., San Diego, CA, and approved September 9, 2010 (received for review March 17, 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 y 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.

bolic disease or the 11 cancer-associated alleles were considered separately. We compared 391 long-lived subjects and 409 youn- ger controls in the 10% tails of the sum of risk allele distribution. The carriers of the 10% upper tail of the sum of risk allele dis- tributions did not have a decreased risk of surviving beyond 85 y of age, because the odds ratio (OR) estimates are close to unity (Tables S2– S4). The 95% confi dence interval (CI) of the OR per extra risk allele ranges from 0.97 to 1.01. Further exploration for different effect sizes and interacting alleles did not reveal any evidence for a subset of alleles associating with longevity via main effects or as interactions.

association aging SNP

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

of long-lived families have a lifelong survival ad- vantage (1, 2) that can be attributed to a lower risk for coronary artery disease, cancer, and type 2 diabetes (3– 5). These observations may be explained by the presence of alleles pro- tecting 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 – (11 13). 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 (12). To in- vestigate 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- fi speci c allele frequencies (Dataset S1).

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

Results

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 sur- vival beyond 85 y of age by comparing 723 nonagenarian siblings (mean age of 94 y) from the LLS (1), representing familial long- lived cases, and 721 unrelated younger controls (mean age of 52 y). We also compared 979 singleton long-lived individuals older than 85 y (mean age of 87 y) of age from the population-based Leiden 85 Plus Study (6, 7) and 1,167 younger controls (mean age of 41 y) from the Netherlands Twin Register (NTR) (8).

Discussion

A lower genetic predisposition for disease in long-lived individ- uals may explain why long-lived families have a delayed age of onset and lower mortality attributable to common age-related – diseases (3 5). Therefore, our aim was to investigate whether the absence of currently known genetic susceptibility alleles is es- sential for survival into old age. Hence, we compared the cu- fi mulative effect of alleles that have convincingly been identi ed as risk factors for cardiovascular disease, type 2 diabetes, and