Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Abstract

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10 −8 ) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Discovery of 42 genome-wide significant loci associated with dyslexia

“…Of 38 associated loci (the 4 remaining were tagged by indels unavailable in validation cohorts), 3 (rs13082684, rs34349354 and rs11393101) were significant at a Bonferroni-corrected level ( P < 0.05/38) in the GenLang consortium GWAS meta-analysis of reading ( n = 33,959) and spelling ( n = 18,514) ability 14 . At P < 0.05, 18 were associated in GenLang, 3 in the NeuroDys case-control GWAS 12 ( n = 2,274 cases), and 5 in the Chinese Reading Study (CRS) of reading accuracy and fluency ( n = 2,270; Supplementary Note ) (Table 1 and Supplementary Tables 3 – 6 ).…”

“…In the largest GWAS of dyslexia to date (>50,000 self-reported diagnoses), we identified 42 significant independent loci. Of these, 14 , and 1 in a Chinese language cohort. Of the significant SNPs, 36% overlapped with variants from general cognitive ability GWAS, consistent with twin studies that find that genetic variation in reading disability is explained by general and reading-specific cognitive ability 10 .…”

“…In the largest GWAS of dyslexia to date (>50,000 self-reported diagnoses), we identified 42 significant independent loci. Of these, 27 represent new associations that have not been uncovered in GWAS of related cognitive traits; 12 of the new associations were validated in the GenLang consortium GWAS meta-analysis of reading/spelling in English and other European languages 14 , and 1 in a Chinese language cohort. Of the significant SNPs, 36% overlapped with variants from general cognitive ability GWAS, consistent with twin studies that find that genetic variation in reading disability is explained by general and reading-specific cognitive ability 10 .…”

A genome wide association study identifies a new variant associated with word reading fluency in Chinese children

“…The copyright holder for this this version posted October 24, 2022. ; https://doi.org/10.1101/2022.10. 23.513381 doi: bioRxiv preprint ability/disability and reading/dyslexia-related cognitive predictors in recent years [18][19][20]. Reading accuracy and reading fluency are two important aspects to account reading ability/disability.…”

“…Other than GWAS with dyslexia, more and more candidate gene studies and GWAS started to investigate genetic correlates with quantitative trait of reading ability/disability and reading/dyslexia-related cognitive predictors in recent years [18][19][20]. Reading accuracy and reading fluency are two important aspects to account reading ability/disability.…”