Abstract
Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
Highlights
Developmental dyslexia (DD) is a neurodevelopmental disorder affecting the ability of learning to read and to spell, in spite of adequate intelligence, educational opportunities, and in the absence of overt neurological and sensorial deficits[1]
Independent association approaching genome-wide significance was observed with rapid automatized naming of letters (RANlet) at rs16928927 (C/T; minor allele frequency (MAF) = 6.5%; p-value = 2.25 × 10−8, major allele (C) β (SE) = −0.4 (0.07)) on 8q12.3
A detailed assessment of six candidate single-nucleotide polymorphism (SNP) previously associated with DD or related cognitive measures in independent studies did not reveal any strong evidence of replication in our cohorts, we found marginal evidence of association of the ROBO1 variant rs12495133 with word spelling (WSpell) (C/A; MAF = 40%; p-value = 0.045, major allele (C) β (SE) = −0.06 (0.03)), with an allelic trend concordant with the original report[22]
Summary
Developmental dyslexia (DD) is a neurodevelopmental disorder affecting the ability of learning to read and to spell, in spite of adequate intelligence, educational opportunities, and in the absence of overt neurological and sensorial deficits[1]. Dyslexic individuals usually have severe and persistent problems in accurate and fluent reading and spelling, and in reading comprehension[3] These problems are often associated with early deficits in neurocognitive skills, such as the ability to recognize and manipulate the phonemic constituents of speech ( known as phoneme awareness, PA), the ability to store such phonemes while reading ( known as phonological short-term memory), or the ability to fast map known visual symbols onto spoken word representations (known as naming speed)[4]. All these abilities show moderate-to-high heritability (40–80%)[5,6,7] and significant genetic correlations with DD5. They represent cognitive indicators of dyslexia risk that are optimally suited for investigating the genetic mechanisms at its basis
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