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. "
    Egyptian Journal of Medical Human Genetics 09/2014; 16(1). DOI:10.1016/j.ejmhg.2014.08.002
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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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    ABSTRACT: X-ray repair cross-complementing group 1 (XRCC1) gene Arg194Trp polymorphism has been reported to be associated with risk of lung cancer in many published studies. Nevertheless, the research results were inconclusive and conflicting. To reach conclusive results, several meta-analysis studies were conducted by combining results from literature reports through pooling analysis. However, these previous meta-analysis studies were still not consistent. Hence, we used an updated and cumulative meta-analysis to get a more comprehensive and precise result from 25 case-control studies searching through the PubMed database up to September 1, 2013. The meta-analysis was carried out by the Comprehensive Meta-Analysis software and the odds ratio (OR) with 95 % confidence interval (CI) was used to estimate the pooled effect. The result involving 8,876 lung cancer patients and 11,210 controls revealed that XRCC1 Arg194Trp polymorphism was not associated with lung cancer risk [(OR = 0.97, 95 %CI = 0.92-1.03) for Trp vs. Arg; (OR = 0.92, 95 % CI = 0.85-0.98) for ArgTrp vs. ArgArg; (OR = 1.07, 95 % CI = 0.92-1.23) for TrpTrp vs. ArgArg; (OR = 0.93, 95 % CI = 0.87-1.00) for (TrpTrp + ArgTrp) vs. ArgArg; and (OR = 1.08, 95 % CI = 0.94-1.25) for TrpTrp vs. (ArgTrp + ArgArg)]. The cumulative meta-analysis showed that the results maintained the same, while the ORs with 95 % CI were more stable with the accumulation of case-control studies. The sensitivity and subgroups analyses showed that the results were robust and not affected by any single study with no publication bias. Relevant studies might not be needed for supporting these results.
    Tumor Biology 03/2014; 35(6). DOI:10.1007/s13277-014-1745-z · 3.61 Impact Factor
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    • "It is widely believed that deviation from HWE may be as a result of genetic reasons including non-random mating, or the alleles reflect recent mutations that have not reached equilibrium, as well as methodological reasons including biased selection of subjects from the population or genotyping errors [34,35]. Because of the reasons of disequilibrium, the results of genetic association studies might be spurious if the distribution of genotypes in the control groups were not in HWE [36,37]. Hence, we carried out subgroup analysis by HWE in controls. "
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    ABSTRACT: The SNP309 polymorphism (T-G) in the promoter of MDM2 gene has been reported to be associated with enhanced MDM2 expression and tumor development. Studies investigating the association between MDM2 SNP309 polymorphism and endometrial cancer risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association. All studies published up to August 2013 on the association between MDM2 SNP309 polymorphism and endometrial cancer risk were identified by searching electronic databases PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature database (CBM). The association between the MDM2 SNP309 polymorphism and endometrial cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Eight case-control studies with 2069 endometrial cancer cases and 4546 controls were identified. Overall, significant increase of endometrial cancer risk was found when all studies were pooled in the meta-analysis (GG vs. TT: OR = 1.464, 95% CI 1.246-1.721, P < 0.001; GG vs. TG + TT: OR = 1.726, 95% CI 1.251-2.380, P = 0.001; GG + TG vs. TT: OR = 1.169, 95% CI 1.048-1.304, P = 0.005). In subgroup analysis by ethnicity and HWE in controls, significant increase of endometrial cancer risks were observed in Caucasians and studies consistent with HWE. In subgroup analysis according to study quality, significant associations were observed in both high quality studies and low quality studies. This meta-analysis suggests that MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility, especially in Caucasian populations. Further large and well-designed studies are needed to confirm this association.
    Journal of Experimental & Clinical Cancer Research 11/2013; 32(1):85. DOI:10.1186/1756-9966-32-85 · 4.43 Impact Factor
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