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On the replication of genetic associations: timing can be everything! |
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| Authors: | Lasky-Su Jessica Lyon Helen N Emilsson Valur Heid Iris M Molony Cliona Raby Benjamin A Lazarus Ross Klanderman Barbara Soto-Quiros Manuel E Avila Lydiana Silverman Edwin K Thorleifsson Gudmar Thorsteinsdottir Unnur Kronenberg Florian Vollmert Caren Illig Thomas Fox Caroline S Levy Daniel Laird Nan Ding Xiao McQueen Matt B Butler Johannah Ardlie Kristin Papoutsakis Constantina Dedoussis George O'Donnell Christopher J Wichmann H-Erich Celedón Juan C Schadt Eric Hirschhorn Joel Weiss Scott T Stefansson Kari Lange Christoph |
| Affiliation: | 1 SUNY Upstate Medical University, Syracuse, NY 13210, USA 2 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA 3 GSF National Research Centre for Environment and Health, Institute of Epidemiology, 85764 Neuherberg, Germany 4 Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-University, 80539 Munich, Germany 5 deCode Genetics, IS-101 Reykjavik, Iceland 6 Divisions of Genetics and Endocrinology, Program in Genomics, Children's Hospital, Boston, MA 02115, USA 7 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 8 Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA 9 Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, 6020 Innsbruck, Austria 10 Division of Pediatric Pulmonology, Hospital Nacional de Niños, PO Box 1654-1000, San José, Costa Rica 11 National Heart, Lung, and Blood Institute and its Framingham Heart Study, Framingham, MA 01702, USA 12 Harvard School of Public Health, Boston, MA 02115, USA 13 Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA 14 Rosetta Inpharmatics, Seattle, WA 98109, USA 15 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 16 Department of Nutrition and Dietetics, Harokopio University, Athens 17671, Greece |
| Abstract: | 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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