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

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.

Opposite Associations between Individual KIAA0319 Polymorphisms and Developmental Dyslexia Risk across Populations: A Stratified Meta-Analysis by the Study Population

“…In other words, examining the association between a single genetic marker and DD risk without taking into account other genetic markers of DD risk and environmental factors correlated with the target susceptibility marker will yield ambiguous results 45 . DD is a complex disease caused by the interaction of various environmental and genetic factors 46 47 . The genetic backgrounds of Asian and Western people are different, and they have long lived in different environments.…”

Visual motion and rapid auditory processing are solid endophenotypes of developmental dyslexia

“…To date, 493 unrelated Italian nuclear families with DD probands have been recruited (Mascheretti et al . ). The ascertainment scheme has been reported in detail elsewhere (Marino et al .…”

“…It is unlikely that a single model connects all the DD-candidate genes and their corresponding proteins at the molecular level; instead, several etiopathogenetic cascades involved in neuronal migration and neurite outgrowth is perhaps a more comprehensive and plausible model for DD (Poelmans et al 2011). Second, the pathways from genes to DD are not straightforward (cf., 'the missing heritability problem') (Maher 2008), and can be influenced by several events, such as incomplete linkage disequilibrium between causal variants and genotyped SNPs (Yang et al 2011), environmental effects, as well as gene-by-gene and gene-by-environment phenomena (Harold et al 2006;Ludwig et al 2008;Mascheretti et al 2013Mascheretti et al , 2015McGrath et al 2007;Powers et al 2013Powers et al , 2016. Taking into account these effects has been shown to improve the phenotypic variance explained by etiological risk factors (Plomin 2013).…”

Complex effects of dyslexia risk factors account for ADHD traits: evidence from two independent samples

“…To assess G × G, we applied a two‐step approach (Mascheretti, Bureau, et al., ): (a) a general linear model equation, whereby the trait is predicted by the main effect of the number of rare alleles of two genes and by the effect of their interaction, and (b) a family‐based association test that takes into account both between‐family and within‐family genetic orthogonal components (De Lobel, Thijs, Kouznetsova, Staessen, & Van Steen, ; Appendix S1). First, all possible pairwise G × G are tested, and then significant G × G pairwises are submitted to family‐based analyses to control for stratification bias and to strengthen the reliability of significant findings.…”

“…However, as of yet, similar frameworks for exploring the pleiotropic effect of putative risk factors have never been used. Indeed, even if G × G and G × E have been investigated independently in DD (Friend et al., ; Harold et al., ; Jacobsen, Kleppe, Johansson, Zayats, & Haavik, ; Kremen et al., ; Ludwig et al., ; Mascheretti, Bureau, Trezzi, Giorda, & Marino, ; Mascheretti et al., ; McGrath et al., ; Powers et al., , ) and ADHD (Jacobsen et al., ; Rosenberg et al., ), to our knowledge, their pleiotropic effects across phenotypes have not been tested.…”