The finding of the linkage to exceptional longevity at chromosome 4 near the MTP gene was the result of a genome-wide scan in 308 extremely long-lived individuals in 137 sib ships with the use of non-parametric linkage analysis.5 Longevity is a complex trait and is probably modulated by multiple genes. Our group has previously shown that mapping a rare dominant genetic variation that reduces hazard of death by half with the use of nonparametric linkage analysis would require a sample of more than 600 long-lived pairs15 to ensure acceptable power. In the case of localization of recessive genes, the power is larger and the method is able to localize recessive genes with relatively small effects with the same sample size (600 pairs). So although the power issue may depend heavily on the true genetic nature in maintaining survival, the results from small-scale sib-pair investigations, such as the study of Puca et al, 5 should be interpreted with caution and should be subject to independent replications. Statis-

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Puca AA, Daly MJ, Brewster SJ et al: A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome

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Geesaman BJ, Benson E, Brewster SJ et al: Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci USA

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cohort: A genetic-epidemiological nationwide survey. Age Age

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tical evidence for an association between an allele and a phenotype theoretically comes from three different situa- tions, the allele itself might be functional, the allele may be correlated with a causative gene nearby or the association is attributable to chance.16 Population stratification can induce important bias, but the original study by Geesaman et al,7 used proactive matching of cases and controls to protect against stratification-induced false positives, so it is unlikely that population stratification is in fact the source of the discrepancy. The results from Geesaman could be F caused by random chance simply a false-positive fluctua- F tion although true population genetic differences or gene–environment differences between the two popula- tions cannot be ruled out.

To conclude, a previous study7 reported a haplotype marker within the MTP gene as a modifier of human lifespan, but our confirmatory study does not support an association between extreme longevity and the Microso- mal Transfer Protein. Replication studies are crucial to cope with the false positive results in mapping human complex trait genes. The fact that our results, based on a large and well-defined sample, fail to confirm the association between the MTP gene and longevity reported by Geesa- man et al illustrates the necessity of replication studies in mapping genes which affect human longevity.

Acknowledgements

This work was supported by the US National Institute on Aging Research Grant NIA-PO1-AG08761, The Danish National Research Foundation.

References

De Benedictis G, Tan Q, Jeune B et al: Recent advances in human gene-longevity association studies. Mech Ageing Dev 2001; 122: 909–920.