Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JPImpact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 163(4): 300-309

University of Ioannina, Yannina, Epirus, Greece
American Journal of Epidemiology (Impact Factor: 5.23). 03/2006; 163(4):300-9. DOI: 10.1093/aje/kwj046
Source: PubMed


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.

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Available from: Muin J Khoury, Aug 27, 2014
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    • "Hence, it seems unlikely that genotyping error is the source of the Hardy–Weinberg disequilibrium observed in our study. Because approximately 10% of all genotype–phenotype association studies show deviation from Hardy–Weinberg equilibrium , the results of our trial cannot be considered ''abnormal'' [5]. A selection bias (population stratification) may have occurred because of inclusion and exclusion criteria of this randomized trial. "

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    • "When we deleted the study reported by Buch et al.[27], which was not according to HWE any more, the heterogeneity of all genetic models were decreased and the results of all five genetic models were of no significance (Table 2). This further indicated that violations and deviations in HWE might be one source of heterogeneity and do largely influence the results [40]. "
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