• Open Access

A novel permutation test for case-only analysis identifies epistatic effects on human longevity in the FOXO gene family

Authors

  • Qihua Tan,

    Corresponding author
    1. Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
    • Epidemiology, Institute of Public Health, University of Southern Denmark, Odense C, Denmark
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  • Mette Soerensen,

    1. Epidemiology, Institute of Public Health, University of Southern Denmark, Odense C, Denmark
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  • Torben A. Kruse,

    1. Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
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  • Kaare Christensen,

    1. Epidemiology, Institute of Public Health, University of Southern Denmark, Odense C, Denmark
    2. Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
    3. Department of Biochemistry and Pharmacology, Odense University Hospital, Odense C, Denmark
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  • Lene Christiansen

    1. Epidemiology, Institute of Public Health, University of Southern Denmark, Odense C, Denmark
    2. Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
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Correspondence

Qihua Tan, Epidemiology, Institute of Public Health, University of Southern Denmark, J. B. Winsløws Vej 9B, DK-5000 Odense C, Denmark. Tel.: 0045 65503536; fax: 0045 65411911; e-mail: qtan@health.sdu.dk

Summary

Genetic interactions or epistasis could make a substantial contribution to variation in human complex traits including longevity. However, detecting epistatic interactions in high dimensional datasets is difficult due to various reasons including multiple testing of correlated tests. We introduce a novel permutation strategy to the case-only analysis of gene-by-gene interaction using multiple SNPs. The method is applied to genes coding for Forkhead box O transcription factors which recently have been associated with human longevity across different populations hypothesizing that epistatic interaction in the regulation and expression of the FOXO gene family could contribute to the human longevity phenotype. Genotype data were collected from 1088 individuals from the Danish 1905 birth cohort aged over 92–93 years with 12 SNPs in the FOXO1a and 15 SNPs in the FOXO3a genes. Our analysis detected a joint effect between rs9486902 in FOXO3a and rs2701858 in FOXO1a that highly significantly contributes to human longevity (OR = 3.23, 95% CI: 2.93–3.53) which is consistent in both males and females. Our results were compared with published studies, and importance of our novel method and findings was discussed.

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