Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 849-858, 03 April 2008
doi:10.1016/j.ajhg.2008.01.018
Article
On the Replication of Genetic Associations: Timing Can Be Everything!
Jessica Lasky-Su1, 2, 17, 
, 
, Helen N. Lyon6, 7, 8, 17, Valur Emilsson5, 14, Iris M. Heid3, 4, Cliona Molony14, Benjamin A. Raby2, Ross Lazarus2, Barbara Klanderman2, Manuel E. Soto-Quiros10, Lydiana Avila10, Edwin K. Silverman2, Gudmar Thorleifsson5, Unnur Thorsteinsdottir5, Florian Kronenberg9, Caren Vollmert3, Thomas Illig3, Caroline S. Fox11, Daniel Levy11, Nan Laird12, Xiao Ding12, Matt B. McQueen13, Johannah Butler6, 7, Kristin Ardlie7, Constantina Papoutsakis16, George Dedoussis16, Christopher J. O'Donnell11, H.-Erich Wichmann3, 4, Juan C. Celedón2, Eric Schadt14, Joel Hirschhorn6, 7, 15, Scott T. Weiss2, Kari Stefansson5 and Christoph Lange2, 12, ,
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
Corresponding authorCorresponding author17 These authors contributed equally to this work.
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. 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 × 10−9, combined p value from pediatric cohorts = 2.21 × 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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