* Marker Position MLS* hlod dom D4S1534 95.0 0.57 0.54 D4S414 100.8 1.53 1.30 D4S2986 105.3 2.78 2.26 D4S1572 108.0 3.07 2.57 D4S411 109.0 3.07 2.60 D4S1564 112.6 3.65 3.26 D4S406 117.1 2.55 2.15 D4S1611 121.6 1.70 1.56 D4S402 124.5 1.39 1.06 D4S2975 126.7 0.94 0.89

Discussion

least their early nineties (4), the degree of excess allele sharing indicates that 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 mecha- nisms 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 (13). The marked decreased frequency of the apoli- poprotein (apo)E « -4 allele among centenarians exemplifies such a mechanism (14). 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 asso- ciated with aging (3). The possibility that we are tracing a locus effecting a single common disease is less likely given recent findings by scientists working with the French Centenarian Study sample set. Simulations performed by Nemani et al. indicate that the allele-sharing method is unable to detect polymorphisms that predispose young individuals to significant mortality and occur « at low frequency, as in the case of carriers of the apoE -4 allele (15). Consistent with this observation, we have not detected any linkage at the apoE or other known disease loci.

MLS and parametric hlod scores were calculated for in the exceptional longevity susceptibility locus relative to markers the chromosome 4 region. Positions are from the Marshfield (http:yyresearch.marshfieldclinic.orgygeneticsyMap_MarkersymapsyIndex- MapFrames.html). Fine mapping at an average of 1 marker every 3 D4S1564. 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. 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.

detecting genes contributing to complex traits (11). In this case, a positive result from an independent parametric analysis could serve as a validity check of the nonparametric findings. In addition, nonparametric methods do not easily allow for the presence of locus heterogeneity. Therefore, multipoint genome- wide affected-only parametric linkage analyses were conducted by using the ALLEGRO program under both a dominant and recessive model with reduced penetrance and allowing for heterogeneity (12).

Alternatives to this linkage study are case-control studies performed on a priori-selected candidate genes hypothesized to effect fundamental mechanisms of aging (14, 16). The drawbacks of such studies include the improbability of picking the right gene to study the myriad of known and unknown genes affecting the process of interest (17). The linkage study described here markedly improves the efficiency of such association studies by defining a region likely to contain polymorphism(s) with signif- icant influence on life span.

The disease allele frequency under each model was deter- mined such that the penetrance model fit a population preva- lence of 5% (0.047 for dominant and 0.30 for recessive). Because we analyzed only affecteds, the penetrance of the susceptible genotypes was set to 1 and to 0.005 for the unsusceptible genotypes (phenocopies). As these penetrance parameters are necessarily based on assumptions about the frequency of non- genetic cases, after performing our analysis with this predefined model, we repeated the analysis by varying the penetrance parameters (penetrance ratio varied from 200:1 to 50:1). These variations on our model had a negligible effect on our results.

Additional association studies with these families and repli- cation 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. Identifica- tion of the 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 was the original dataset. Of 1,000 replicates, 26 had a lod score . 5 3.3 under the dominant model (P 0.026), and 77 had a lod . 5 score 2.9 under the recessive model (P 0.077). Because two inheritance models were evaluated, these parametric results are

We thank Drs. Dale Nyholt, Eric Lander, and Jurg Ott for their helpful remarks. We also thank the remarkable family members who partici- pated in this study for their time and assistance in our phenotypic data and genetic material gathering efforts. L.M.K. is a Howard Hughes Institute Investigator and an Ellison Medical Foundation Senior Scholar. T.P. is supported by grants from the Alzheimer’s Association Darrell and Jane Phillippi Faculty Scholar Award, the Paul Beeson Faculty Scholar in Aging Research Award (the American Federation for Aging Research and the Alliance for Aging Research), the Institute for the Study of Aging, the National Institute on Aging (1R01AG18721, 1R21AG16916), and the Retirement Research Foundation.

Bell, F., Wade, A. & Goff, S. (