A total of 42 independent genome-wide significant loci were found to be associated with dyslexia, according to a study published in Nature Genetics.
Dyslexia is a neurodevelopmental disorder characterized by severe reading difficulties and is often associated with other psychiatric or developmental disorders. Dyslexia can affect up to 17.5% of the population. Previous research into the genetic underpinnings of dyslexia have produced insufficiently replicated results.
To reassess the role of genetics in dyslexia, researchers sourced data from 23andMe, Inc. Individuals who answered “yes” when asked whether they had ever been diagnosed with dyslexia (n=51,800) were compared with those (n=1,087,070) who answered “no” in the principal genome-wide association study (GWAS). Data from a published meta-analysis which included 2274 dyslexia cases from Europe (NeuroDys); 2270 children from China with reading accuracy and fluency data (CRS); and children and adolescents from Europe, the United States, and Australia (GenLang) with reading (n=33,959) and spelling (18,514) performance scores were used as validation cohorts.
The researchers developed a dyslexia polygenic risk score (PGS) using significant genetic variants and evaluated its power among 2 Australian population-based samples (adults: n=1163; adolescents: n=1647) and 2 cohorts enriched for reading difficulties (UKdys: n=930; CLDRC: n=717).
The study participants were aged between 18 to 110 years old and those with dyslexia were younger (mean, 49.6 years) than control individuals (mean, 51.7 years). In both individuals with dyslexia and control individuals, there were more women than men participants.
A total of 42 independent loci were significant at the genome-wide significance level of P <5×10-8 and 64 trended toward significance at a level of P <10x-6. The researchers performed age- and gender-specific GWAS, finding high linkage disequilibrium (LD) score regression (LDSC) genetic correlations of 0.97 (95% CI, 0.91-1.02; P =2.32×10-268) and 0.91 (95% CI, 0.86-0.96; P =8.26×10-253) between younger and older and men and women, respectively.
The candidate variants from the main analysis were all autosomal except for 1. A subset of 17 candidates were in high LD with variants that have been associated with other phenotypes, including cognitive and educational traits (n=15). The remaining 27 variants have not previously been associated with another trait.
The gene-based analysis identified a total of 173 significant genes with no enriched biological pathways. The estimated heritability of dyslexia was 0.152 assuming a 5% prevalence and 0.189 assuming a 10% prevalence.
After removing insertions and deletions, the remaining 38 variants were evaluated in the validation datasets. A total of 18 variants were significant in the GenLang data, 5 in the CRS data, 3 in the NeuroDys data, and 3 were related with the reading and spelling performance scores from GenLang.
The dyslexia PRS explained 3.6% of the variance in reading and spelling using data from Australia and 3.7% (UKdys) and 5.6% (CLDRC) of the variance in word recognition tests.
This study may have been biased by relying on self-reported dyslexia diagnoses.
The researchers concluded, “We report 42 new independent genome-wide significant loci associated with dyslexia, 27 of which have not been associated with cognitive-educational traits and should be prioritized for follow up as dyslexia candidates.”
Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.
Doust C, Fontanillas P, Eising E, et al. Discovery of 42 genome-wide significant loci associated with dyslexia. Nat Genet. Published online October 20, 2022. doi:10.1038/s41588-022-01192-y