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An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia

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Abstract

Even if substantial heritability has been reported and candidate genes have been identified extensively, all known marker associations explain only a small proportion of the phenotypic variance of developmental dyslexia (DD) and related quantitative phenotypes. Gene-by-gene interaction (also known as “epistasis”—G × G) triggers a non-additive effect of genes at different loci and should be taken into account in explaining part of the missing heritability of this complex trait. We assessed potential G × G interactions among five DD candidate genes, i.e., DYX1C1, DCDC2, KIAA0319, ROBO1, and GRIN2B, upon DD-related neuropsychological phenotypes in 493 nuclear families with DD, by implementing two complementary regression-based approaches: (1) a general linear model equation whereby the trait is predicted by the main effect of the number of rare alleles of the two genes and by the effect of the interaction between them, and (2) a family-based association test to detect G × G interactions between two unlinked markers by splitting up the association effect into a between- and a within-family genetic orthogonal components. After applying 500,000 permutations and correcting for multiple testing, both methods show that G × G effects between markers within the DYX1C1, KIAA0319/TTRAP, and GRIN2B genes lower the memory letters composite z-score of on average 0.55 standard deviation. We provided initial evidence that the effects of familial transmission of synergistic interactions between genetic risk variants can be exploited in the study of the etiology of DD, explain part of its missing heritability, and assist in designing customized charts of individualized neurocognitive impairments in complex disorders, such as DD.

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Acknowledgments

We thank all the parents and children who took part in this study. We really thank Dr. Chantal Mérette for her helpful suggestions. We express our gratitude to Dr. Maria Rosaria Cellino, Lisa Meneghello and Elisabetta Furioni for helping in data collection. We are grateful to two anonymous reviewers for having provided valuable comments. Finally, we thank Harold Gaboury for English text revision. All authors reported no conflicts of interest. Dr. Alexandre Bureau was supported by a research fellowship from the Fonds de recherche du Québec—Santé.

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Authors and Affiliations

  1. Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, 23842, Italy

    S. Mascheretti, V. Trezzi & C. Marino

  2. Centre de recherche de l’Institut universitaire en santé mentale de Québec, Quebec City, Canada

    A. Bureau & C. Marino

  3. Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec City, Canada

    A. Bureau

  4. Molecular Biology Lab, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Italy

    R. Giorda

  5. Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Quebec City, Canada

    C. Marino

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  1. S. Mascheretti
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  4. R. Giorda
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Correspondence to S. Mascheretti.

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Mascheretti, S., Bureau, A., Trezzi, V. et al. An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia. Hum Genet 134, 749–760 (2015). https://doi.org/10.1007/s00439-015-1555-4

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