Genetics. Published Articles Ahead of Print: December 30, 2005, Copyright © 2005
doi:10.1534/genetics.105.050914


A more recent version of this article appeared on March 1, 2006.

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Genetic association analysis of human longevity in cohort studies of elderly subjects: an example of PON1 gene in the Danish 1905 birth cohort

Qihua Tan 1*, Lene Christiansen 2, Lise Bathum 1, Shuxia Li 2, Torben A. Kruse 1 and Kaare Christensen 2

1 Odense University Hospital
2 University of Southern Denmark

* To whom correspondence should be addressed. E-mail: qihua.tan{at}ouh.fyns-amt.dk.

Submitted on September 9, 2005
Revised on October 13, 2005
Accepted on 13 December 2005


Abstract

Although the case-control or the cross-sectional design has been popular in genetic association studies of human longevity, such a design is prone to false positive results due to sampling bias and potential secular trend in gene-environment interactions. In order to avoid these problems, the cohort or follow-up study design has been recommended. With the observed individual survival information, the Cox regression model has been used for single locus data analysis. In this paper, we present a novel survival analysis model that combines population survival with individual genotype and phenotype information in assessing the genetic association with human longevity in cohort studies. By monitoring the changes in the observed genotype frequencies over the follow-up period in a birth cohort, we are able to assess the effects of the genotypes and /or haplotypes on individual survival. With the estimated parameters, genotype and/or haplotype specific survival and hazard functions can be calculated without any parametric assumption on the survival distribution. In addition, our model estimates haplotype frequencies in a birth cohort over the follow-up time, which is not observable in the multi-locus genotype data. A computer simulation study was conducted to specifically assess the performance and power of our haplotype based approach for given risk and frequency parameters under different sample sizes. Application of our method to paraoxonase 1 genotype data detected a haplotype that significantly reduces carriers' hazard of death and thus reveals and stresses the important role of genetic variation in maintaining human survival at advanced ages.

Key Words: PON1 gene, association study, human longevity, old cohort