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Replication validity of genetic association studies


The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale1,2. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity3,4. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.

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Figure 1: Correlation between the odds ratio (OR) in the first study/studies and in subsequent research.
Figure 2: Evolution of the strength of an association as more information is accumulated.

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This work was supported in part by a grant from the General Secretariat for Research and Technology, Greece, funded through the European Union.

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Correspondence to John P.A. Ioannidis.

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Ioannidis, J., Ntzani, E., Trikalinos, T. et al. Replication validity of genetic association studies. Nat Genet 29, 306–309 (2001).

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