Genetic neurodevelopmental clustering and dyslexia

Abstract

AbstractDyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling despite adequate education. Dyslexia is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). The purpose of this paper was to elucidate how genetic factors predisposing to dyslexia correlate with risk for other neurodevelopmental and psychiatric traits. A large-scale genome-wide association study (GWAS) of dyslexia diagnosis self-report (51,800 cases and ∼1.1 million controls), together with GWAS of ADHD, autism, Tourette syndrome, anxiety, depression, schizophrenia, bipolar, obsessive compulsive disorder, anorexia, were analysed using Genomic Structural Equation Modelling (GenomicSEM) to construct a genomic structural model. The final model consisted of five correlated latent genomic factors described as F1) internalising disorders, F2) psychotic disorders, F3) compulsive disorders, F4) neurodevelopmental conditions, and F5) attention and learning difficulties, which includes ADHD and dyslexia. This latent factor was moderately correlated with internalising disorders (.40) and, to a lesser extent, with neurodevelopmental conditions (.25) and psychotic disorders (.17), and negatively with compulsive disorders (-.16). Unlike ADHD, most of the genomic variance in dyslexia was unique, suggesting a more peripheral relation to psychiatric traits. We further investigated genetic variants underlying both dyslexia and ADHD. This implicated 49 loci (40 of which were not reported in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits). Our study has discovered novel pleiotropic variants and confirms via GenomicSEM the heightened genetic relation between dyslexia and ADHD versus other psychiatric traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia, for which there are currently no large-scale GWAS, will allow a more clear definition of the attention and learning difficulties genomic factor, yielding further insights into factor structure and pleiotropic effects.