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Lasky-Su, J.* ; Lyon, H.N.* ; Emilsson, V.* ; Heid, I.M. ; Molony, C.* ; Raby, B.A.* ; Lazarus, R.* ; Klanderman, B.* ; Soto-Quiros, M.E.* ; Avila, L.* ; Silverman, E.K.* ; Thorleifsson, G.* ; Thorsteinsdottir, U. ; Kronenberg, F.* ; Vollmert, C. ; Illig, T. ; Fox, C.S.* ; Levy, D.* ; Laird, N.* ; Ding, X.* ; McQueen, M.B.* ; Butler, J.* ; Ardlie, K.* ; Papoutsakis, C.* ; Dedoussis, G.* ; O'Donnell, C.J.* ; Wichmann, H.-E. ; Celedón, JC.* ; Schadt, E.* ; Hirschhorn, J.* ; Weiss, S.T.* ; Stefansson, K.* ; Lange, C.*

On the replication of genetic associations: Timing can be everything!

Am. J. Hum. Genet. 82, 849-858 (2008)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 82, Heft: 4, Seiten: 849-858 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)