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The Augmented Classical Twin Design: Incorporating Genome‐Wide Identity by Descent Sharing Into Twin Studies in Order to Model Violations of the Equal Environments Assumption

A Correction to this article was published on 27 May 2021

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Abstract

The Classical Twin Method (CTM) compares the similarity of monozygotic (MZ) twins with that of dizygotic (DZ) twins to make inferences about the relative importance of genes and environment in the etiology of individual differences. The design has been applied to thousands of traits across the biomedical, behavioral and social sciences and is arguably the most widely used natural experiment known to science. The fundamental assumption of the CTM is that trait relevant environmental covariation within MZ pairs is the same as that found within DZ pairs, so that zygosity differences in within-pair variance must be due to genetic factors uncontaminated by the environment. This equal environments assumption (EEA) has been, and still is hotly contested, and has been mentioned as a possible contributing factor to the missing heritability conundrum. In this manuscript, we introduce a new model for testing the EEA, which we call the Augmented Classical Twin Design which uses identity by descent (IBD) sharing between DZ twin pairs to estimate separate environmental variance components for MZ and DZ twin pairs, and provides a test of whether these are equal. We show through simulation that given large samples of DZ twin pairs, the model provides unbiased estimates of variance components and valid tests of the EEA under strong assumptions (e.g. no epistatic variance, IBD sharing in DZ twins estimated accurately etc.) which may not hold in reality. Sample sizes in excess of 50,000 DZ twin pairs with genome-wide genetic data are likely to be required in order to detect substantial violations of the EEA with moderate power. Consequently, we recommend that the Augmented Classical Twin Design only be applied to datasets with very large numbers of DZ twin pairs (> 50,000 DZ twin pairs), and given the strong assumptions relating to the absence of epistatic variance, appropriate caution be exercised regarding interpretation of the results.

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Acknowledgements

D.M.E. and S.E.M are funded by Australian National Health and Medical Research Council Senior Research Fellowships (APP1137714 and APP 1103623). B.L.M is grateful for support from Queensland University of Technology through a QUT Postgraduate Research Scholarship.

Funding

D.M.E. and S.E.M are funded by Australian National Health and Medical Research Council Senior Research Fellowships (APP1137714 and APP 1103623).

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Correspondence to David M. Evans.

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Liang‑Dar Hwang, Brittany L. Mitchell, Sarah E. Medland, Nicholas G. Martin, Michael C. Neale and David M. Evans report no conflicts of interest.

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Hwang, LD., Mitchell, B.L., Medland, S.E. et al. The Augmented Classical Twin Design: Incorporating Genome‐Wide Identity by Descent Sharing Into Twin Studies in Order to Model Violations of the Equal Environments Assumption. Behav Genet 51, 223–236 (2021). https://doi.org/10.1007/s10519-021-10044-0

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Keywords

  • Twin studies
  • Equal environment assumption
  • Heritability
  • Identity by descent