Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

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.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

“…The datasets involved in the present study were collected in nine different populations of European ancestry, with six different languages (see Table 1). Subsets have already been tested for association with continuous reading-related traits [28]. Ethical approval was obtained for each cohort at the local level, and written informed consent was obtained for all the participants or their parents.…”

“…DD and readingrelated cognitive traits have also been investigated via genome-wide association studies (GWAS), which involve analyses of many single-nucleotide polymorphisms (SNPs) spread across the genome. A few such studies have been reported, using either a case-control design [23][24][25] or a continuous trait analysis approach [26][27][28][29][30]. However, only two of these studies identified associations that met criteria for genome-wide significance [27,28].…”

“…A few such studies have been reported, using either a case-control design [23][24][25] or a continuous trait analysis approach [26][27][28][29][30]. However, only two of these studies identified associations that met criteria for genome-wide significance [27,28]. The first was a GWAS of multiple cognitive skills related to reading ability, which revealed a genome-wide significant association at rs17663182 (MIR924HG; 18q12.2) with rapid automatized naming (RAN), in nine cohorts of reading-impaired and typically developing subjects of European ancestry (maximum N = 3468) [28].…”

“…However, only two of these studies identified associations that met criteria for genome-wide significance [27,28]. The first was a GWAS of multiple cognitive skills related to reading ability, which revealed a genome-wide significant association at rs17663182 (MIR924HG; 18q12.2) with rapid automatized naming (RAN), in nine cohorts of reading-impaired and typically developing subjects of European ancestry (maximum N = 3468) [28]. More recently, in a north-American cohort of non-European ancestry (N = 1331), Truong et al [27] identified a genome-wide significant multivariate association of rs1555839 (10q23.31; upstream from the RPL7P34 gene) with RAN and rapid alternating stimulus, and replicated the association with RAN in an independent cohort of European ancestry [27].…”

“…Here, we carried out a case-control GWAS meta-analysis involving 2274 dyslexia cases and 6272 controls from nine different countries that partly overlap with those from the prior Gialluisi et al study of continuous traits (≤2500 overlapping samples) [28]. We performed association testing at the single variant, gene, and pathway level, and estimated SNP-based heritability.…”