Our definition of familial longevity (elevated FEL) assumes a dominant or additive model of inheritance. As a consequence, our selection criteria for affected individuals (and their familial relationship networks) are less sensitive for identifying potential recessive traits than dominant or additive traits. The familial recurrence pattern expected for a recessive trait (sib pairs scattered throughout a pedigree), would in most cases result in higher than expected FEL, particularly in the large sibships typical of the UPDB. Nevertheless, our study has substantially less power to identify loci with recessive effects on longevity: only 63 affected sib pairs are informative with respect to recessively inherited factors; while 607 pairs are potentially informative for dominant or additive inheritance.

It is likely that variants at many loci contribute to the heritability of longevity in humans. Our independent replication of the 3p22- 24 linkage peak originally reported by Boyden and Kunkel [1] should help focus the search for variants associated with longevity in this relatively small region. Advances in DNA sequencing make it practical to rapidly sequence the exons in the region, or the entire region, and hence identify the variant(s) responsible for the observed linkage signal. Other regions identified in one or both of these studies also deserve further scrutiny.

We have recently described patterns of gene expression that are associated with human longevity and aging [43]; now we can try to narrow the set of longevity-associated candidate variants at the 3p locus by searching for markers (microsatellites or SNPs) in the same 3p region that are associated with variation in gene expression patterns that are also associated with longevity. Although in principle this requires a complete set of GWAS data for each expression quantitative trait locus (or eQTL) of interest, several established data repositories for genome-wide eQTL studies [44,45], should greatly simplify the process.

Acknowledgments

We thank Alison Fraser, Diana Lane Reed, and Geri Mineau for valuable assistance in managing the data.

Author Contributions

Conceived and designed the experiments: RAK EO RMC KMB KRS. Performed the experiments: RAK EO RMC. Analyzed the data: RAK EO KMB. Contributed reagents/materials/analysis tools: RAK RMC KRS. Wrote the paper: RAK EO RMC.

The FLAG study differs from the HMS and other studies of exceptional longevity in several important respects. We ascer- tained subjects on the basis of both familial longevity and personal

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