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American Journal of Epidemiology Advance Access originally published online on January 12, 2006
American Journal of Epidemiology 2006 163(4):300-309; doi:10.1093/aje/kwj046
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Meta-Analysis

Impact of Violations and Deviations in Hardy-Weinberg Equilibrium on Postulated Gene-Disease Associations

Thomas A. Trikalinos1,2, Georgia Salanti3,4, Muin J. Khoury5 and John P. A. Ioannidis1,2,6

1 Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
2 Department of Medicine, Tufts University School of Medicine, Boston, MA
3 Biostatistics Unit, Medical Research Council, Cambridge, United Kingdom
4 Cambridge Genetics Knowledge Park, Cambridge, United Kingdom
5 Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, GA
6 Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece

Correspondence to Dr. John P. A. Ioannidis, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece (e-mail: jioannid{at}cc.uoi.gr).

The authors evaluated whether statistically significant violations of Hardy-Weinberg equilibrium (HWE) or the magnitude of deviations from HWE may contribute to the problem of replicating postulated gene-disease associations across different studies. Forty-two gene-disease associations assessed in meta-analyses of 591 studies were examined. Studies with disease-free controls in which HWE was violated gave significantly different results from HWE-conforming studies in five instances. Exclusion of the former studies resulted in loss of statistical significance of the overall meta-analysis in three instances and more than a 10% change in the summary odds ratio in six. Exclusion of HWE-violating studies changed the formal significance of the estimated between-study heterogeneity in three instances. After adjustment for the magnitude of the deviation from HWE for the controls, formal significance was lost in another three instances. Studies adjusted for the magnitude of deviation from HWE tended to become more heterogeneous among themselves, and, for seven gene-disease associations, between-study heterogeneity became significant, while it was not so in the unadjusted analyses. Gene-disease association studies and meta-analyses thereof should routinely scrutinize the potential impact of HWE violations as well as nonsignificant deviations from the exact frequencies expected under HWE. Postulated genetic associations with modest-sized odds ratios and borderline statistical significance may not be robust in such sensitivity analyses.

association; bias (epidemiology); genes; genetics; meta-analysis

Abbreviations: HWE, Hardy-Weinberg equilibrium; ID, (operational) identification number


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