Note: The text was processed to correct spelling errors, split combined words, eliminate redundancies and correct grammatical errors. No changes were made to the original content or context of the text.dataset confirms that the genetic risk profiles of centenarians are more similar to each other than to the controls (Figure S11), indicating a common genetic basis for exceptional longevity. Our results also suggest that different combinations of longevity associated variants may contribute to exceptional longevity in different individuals, and that a subset of SNPs may be optimal for classifying some subjects but not others. Overall, our study provides further evidence that exceptional longevity is a complex trait determined by a combination of genetic and environmental factors, and highlights the importance of studying the genetics of exceptional longevity to identify potential targets for interventions to extend healthy aging.profiles to predict exceptional longevity. The study identified 15 clusters with eight or more subjects, and approximately 35% of profiles clustered in groups of seven or less. Cluster analysis was used to group the genetic risk profiles into prototypical signatures, and it was investigated whether groups of centenarians with particular genetic risk profiles shared specific age-related sub-phenotypes. The specificity of the profiles in characterizing exceptional longevity was examined by generating genetic risk profiles of the control subjects in the discovery set and using cluster analysis to group them. 

Only five subjects had profiles that predicted exceptional longevity with more than 90% posterior probability, and other clusters with more than eight subjects showed that the majority of these profiles match either the lack of a predictive (predictive) or cluster C26 (the least predictive). Cluster analysis identified 26 groups of eight to 94 centenarians (90% of the discovery set) with similar genetic risk profiles, while 10% of the centenarians had rare profiles that occur in groups of seven centenarians or less. 

The prototypical genetic risk profiles associated with each cluster are informative displays of the longevity associated variants and represent different genetic signatures of exceptional longevity. While the ensemble of genetic risk models provides a global estimate of the probability of exceptional longevity, the pattern longevity associated variants of clusters C24C25 in Figure S11. The most predictive genetic signatures that characterize exceptional longevity are rare amongst control subjects, and only 0.6% of the genetic signatures of control subjects have a posterior probability of exceptional longevity .0.95. 

The study observed a similar result when comparing the survival of centenarians with the most predictive signatures in the merged replication sets (R1 and R2), and when comparing the survival of centenarians with the most and least predictive signatures (R1 and R15). However, not all signatures correlated with different survival, for example, centenarians with signatures C1 and C3 did not demonstrate different survival. Preliminary analyses provided in the supplementary material suggest that the different genetic signatures of exceptional longevity associate with varying prevalences and ages of onset of various age-related diseases. 

Interestingly, the patterns of genetic risk profiles that cluster into genetic signatures distinctly differ from clusters of genetic risk profiles generated from SNPs selected at random. It was also investigated if some clusters were enriched for specific ethnicities, but no clusters showed enrichment for any specific European ethnicity. The study investigated whether different genetic signatures correlate with different life spans, and some genetic signatures were indeed associated with significantly different life spans. 

For 17 of the 28 centenarians in cluster C26 who lack almost all the longevity associated variants discovered in this study, information about familial longevity was available. Twenty-five percent (n=5) had more than 50% of siblings who survived past the age of 90 and some had evidence for longevity as shown in some pedigrees in Figure S18. This could indicate that such families have more private or rare variants not captured by either the genotyping or the model.