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Sebastiani P, Solovieff N, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT, Perls TT. Genetic signatures of exceptional longevity in humans. Science. 2010 Jul 1;2010 PubMed. RETRACTED
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Institute of Neurology, UCL
My view of this study is that it is generally underpowered and that, apart from alleles with large effect sizes, it will be not reliable. The Manhattan plot shows that only six SNPs exceeded the generally accepted level of significance of 10-7 to 10-8 (Figure S5), and none of these had the comforting “climbing tower” of less well-defined SNPs to indicate that they are part of a haplotype block showing association (as one of many of the examples of this, see the Simón-Sánchez et al., 2009 SNCA “climbing towers” in their Nature Genetics study of Parkinson’s disease). This does not mean the associations are wrong, but it does mean they may not be reliable. The replication study is an order of magnitude too small.
A general rule is, the more complex the statistical analysis, the less reliable the outcome, because one does not know how many other complex statistical algorithms were tried. The way to do GWAS is to do simple chi squareds across the SNPs, apply a conservative Bonnferroni (10-7) and believe that, given no genotyping confounders. “Real” hits usually (but by no means always) have “climbing towers of less associated SNPs on each side based on the local haplotype structure.
In this GWAS, some hits are likely to be real (ApoE, e.g., which has such an enormous effect on AD risk that it is likely, and has previously been shown, to have an effect on longevity). In general, AD genes like, for example, CLU, will have such a small effect on AD risk (odds ratio 1.2) that their effect on longevity will be really small unless they have other effects on other diseases, too.
References:
Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, Van Der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet. 2009 Dec;41(12):1308-12. PubMed.
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