Database frequencies from the d'Etude du Polymorphisme Humain (Paris) were analyzed. In regions with suggestive linkage, a higher-density map was used to identify genotypes implying double recombinants, and raw data were reexamined or retyped. The genome screen analyzed 308 individuals from 137 families and identified a highly suggestive region on chromosome 4 between D4S1572 and D4S406 (MLS 2.67). Fine mapping at an average of 1 marker every 3 cM in a 20-cM region around this peak resulted in an increased MLS (3.65) at marker D4S1564 (see Table 1). To estimate the significance of the observed linkage to chromosome 4, simulations were designed under the hypothesis of no linkage that matched the family structure and marker heterozygosity of the study. One thousand genome scans were simulated with a genome-wide map density of 1 marker every 3 cM, and in only 44 of those scans was the observed MLS of 3.65 exceeded (P = 0.044).

Previous studies suggest that parametric linkage analyses using both dominant and recessive inheritance models may be more powerful than nonparametric studies in some cases for detecting genes contributing to complex traits. An obvious consequence of studying exceptional longevity is that neither unaffected family members nor parents can be appropriately summarized and corrected by multiplying the more significant associated P value by two, thus producing a final parametric P value of 0.052. These analyses provide significant evidence for heterogeneity, with odds in favor of heterogeneity of 1,800:1. For this dataset and trait, parametric and nonparametric analyses corroborate each other and demonstrate that the results are robust to different sets of assumptions.

Table 1 shows the nonparametric MLS and parametric hlod scores within the exceptional longevity susceptibility locus relative to markers in the chromosome 4 region. A dropoff of 1.5 in the MLS score on either side of the peak defines the area in which we can be 95% confident the gene resides. A dropoff in the MLS of 2 on either side of the peak is observed in a region encompassed by D4S414 and D4S1611. The MLS scores in this and the hlod scores under the dominant model are shown.

A locus in the D4S1564 region could explain 1.65-fold of that risk, and thus a more modest common polymorphism might be inferred. A number of genetic mechanisms are likely to be at play in effecting such an influence. A relative lack of polymorphisms predisposing to age-associated diseases appears to be one prerequisite to achieving exceptional old age. The marked decreased frequency of the apolipoprotein (apo)E-4 allele among centenarians exemplifies such a mechanism. Another prerequisite may be some degree of genetic control over how fast a person ages and the consequent impact on susceptibility to a myriad of diseases normally associated with aging.

Alternatives to this linkage study are case-control studies performed on a priori-selected candidate genes hypothesized to affect fundamental mechanisms of aging. The drawbacks of such studies include the improbability of picking the right gene to study among the myriad of known and unknown genes affecting the process of interest. The linkage study described here improves the efficiency of such association studies by defining a region likely to contain polymorphism(s) with significant influence on life span.

Additional association studies with these families and replication of these results with an independent data set should facilitate the positional cloning of a gene that influences the ability to age well and achieve exceptional longevity. Identification of genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.

The finely mapped region of chromosome 4 provided the strongest results, with a maximum heterogeneity logarithm of odds (hlod) of 3.3 under the dominant model (with 57% of families linked) and a maximum hlod of 2.9 under the recessive model (with 45% of families linked), both occurring at marker D4S1564. Empiric P values were determined by genome-wide simulations. One thousand unlinked replicates were generated to match the actual study. These replicates were analyzed exactly as the original dataset. Of 1,000 replicates, 26 had a lod score ≥3.3 under the dominant model (P = 0.026), and 77 had a lod score ≥2.9 under the recessive model (P = 0.077). Because two inheritance models were evaluated, these parametric results are appropriately summarized and corrected by multiplying the more significant associated P value by two, thus producing a final parametric P value of 0.052.

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