Power of non‐parametric linkage analysis in mapping genes contributing to human longevity in long‐lived sib‐pairs

Abstract

This report investigates the power issue in applying the non-parametric linkage analysis of affected sib-pairs (ASP) [Kruglyak and Lander, 1995: Am J Hum Genet 57:439-454] to localize genes that contribute to human longevity using longlived sib-pairs. Data were simulated by introducing a recently developed statistical model for measuring marker-longevity associations [Yashin et al., 1999: Am J Hum Genet 65:1178-1193, enabling direct power comparison between linkage and association approaches. The non-parametric linkage (NPL) scores estimated in the region harboring the causal allele are evaluated to assess the statistical power for different genetic (allele frequency and risk) and heterogeneity parameters under various sampling schemes (age-cut and sample size). Based on the genotype-specific survival function, we derived a heritability calculation as an overall measurement for the effect of causal genes with different parameter settings so that the power can be compared for different modes (dominant, recessive) of inheritance. Our results show that the ASP approach is a powerful tool in mapping very strong effect genes, both dominant and recessive. To map a rare dominant genetic variation that reduces hazard of death by half, a large sample (above 600 pairs) with at least one extremely long-lived (over age 99) sib in each pair is needed. Again, with large sample size and high age cut-off, the method is able to localize recessive genes with relatively small effects, but the power is very limited in case of a dominant effect. Although the power issue may depend heavily on the true genetic nature in maintaining survival, our study suggests that results from small-scale sib-pair investigations should be referred with caution, given the complexity of human longevity. & 2004 Wiley-Liss, Inc.

A novel sampling design to explore gene-longevity associations: the ECHA study

“…On the whole, the novel design resulted in more complexity and less efficiency in revealing gene-longevity associations in comparison with classic non-parametric approaches. 32,33,37 In conclusion, the ECHA study failed to evidence differences of IBD haplotype sharing in cousin-pairs born from concordant and discordant sib-pairs. It is likely that a larger sample size was required.…”

“…However, despite the strong phenotypic selection, the results of IBD analyses did not reveal significant differences between concordant and discordant families. These negative findings, which contrast with the significant gene-longevity associations found by case -control studies, are most likely explained by sample sizes inadequate to reveal small genetic effects, 33 which are further smoothed when searched in the children of the probands and their cousins (one generation away from the one selected). A further confusing effect may have been played by TRD, which has been observed in our samples for both the studied chromosomal regions.…”

“…31,32 First, because of the effects played on lifespan by social and economic factors, longevity is a phenotype whose definition may change according to the place and year of birth of the cohort; second, true controls in candidate-gene association studies are missing; third, non-parametric linkage analyses require large sample sizes whose statistical power varies according to the dominant/recessive effect of the gene; 33 and, finally, longitudinal studies in which cohorts of individuals are followed over time are very difficult to realize. By comparing genetic similarity in cousin-pairs born from sibships of long-lived subjects (concordant sib-pairs) with cousin-pairs born from sibships in which a single subject attained longevity (discordant sib-pairs), the ECHA design aimed at controlling for potential confounding effects of stratification and genetic demographic shifts in the communities from which the subjects were sampled.…”

Multidisciplinary Approaches in Genetic Studies of Human Aging and Longevity

“…[59] studied the efficiency of the ASP approach and found that the method is powerful in mapping rare recessive genes but has very low power in locating dominant genes. Tan et al [60] reevaluated the power issue of the method in longevity study and reported that a sample size of over 600 long-lived pairs (centenarians and their siblings over age 90)…”

“…The small proportion of the extremely long-lived ASPs is more genetically selected than the majority who are just above the threshold. This is also indicated by the increased IBD sharing at older ages in the region harboring a beneficial gene [60]. It should be possible to increase the power of non-parametric linkage by introducing an optimal weighing scheme to the sharing for each pair based on a function of their ages.…”