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Impact of Hardy–Weinberg equilibrium deviation on allele-based risk effect of genetic association studies and meta-analysis

  • GENETIC EPIDEMIOLOGY
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Abstract

Deviations from Hardy–Weinberg equilibrium (HWE) in control subjects may bias the estimates of genetic effects in genetic association studies (GAS) and meta-analysis. A large empirical evaluation was carried out to evaluate the impact of HWE deviation and explore the effect of variance adjustment for the allele-based odds ratio in 833 individual GAS and 72 meta-analyses. In individual GAS, the variance adjustment for any deviation from HWE resulted in stronger associations, and 10 GAS (1%) became significant (P < 0.05). One hundred sixteen GAS (14%) showed significant deviation from HWE (P HWE < 0.05); however, only 37 GAS (4%) had more than 90% power to detect significant deviation from HWE at the 5% level. In meta-analyses, adjustment for any deviation from HWE improved the significance in 53 meta-analyses (74%). Then, a formal statistical significance (P < 0.05) was revealed for one previously negative meta-analyses whereas one meta-analysis lost its significance. Between-study heterogeneity was enhanced in 50 meta-analyses (69%). None of the meta-analyses lost the significance of heterogeneity (P Q  < 0.10) whereas in one meta-analysis, the non significant heterogeneity became significant. Sensitivity analysis for studies not conforming to HWE (P HWE < 0.05) was applied to 45 meta-analyses (69%). Then, the significance of association was increased in 26 the meta-analyses (58%) and one meta-analysis became significant (P < 0.05) whereas seven meta-analyses (16%) were no longer significant. Adjustment for HWE deviation could be an effective strategy for dealing with HWE violations in GAS and meta-analyses.

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Authors and Affiliations

  1. Department of Biomathematics, University of Thessaly School of Medicine, 2 Panepistimiou Str, Biopolis, Larissa, 41110, Greece

    Elias Zintzaras

  2. Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA

    Elias Zintzaras

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  1. Elias Zintzaras
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Correspondence to Elias Zintzaras.

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Zintzaras, E. Impact of Hardy–Weinberg equilibrium deviation on allele-based risk effect of genetic association studies and meta-analysis. Eur J Epidemiol 25, 553–560 (2010). https://doi.org/10.1007/s10654-010-9467-z

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  • DOI: https://doi.org/10.1007/s10654-010-9467-z

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