Genome-wide association 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 capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, 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, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 × 10−8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13–0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.

Brain structure, phenotypic and genetic correlates of reading abilities

“…This lack of concordance may be partially explained by the fact that the UK Biobank GWASes we used here were run adjusting for head size (Smith et al, 2021), while the ENIGMA meta-analysis did not correct for it (Grasby et al, 2020). Another recent GWAS meta-analysis of reading- and language-related traits (Eising et al, 2021) found a significant genetic correlation between the reading and the CSA of the banks of the superior temporal sulcus (STS), which partially overlaps the lateral STG we report here. They used the same UK Biobank GWAS resouce used in the present study but a different brain parcellation (Smith et al, 2021) to compute the genetic correlations between the reading and language GWAS meta-analysis and 58 structural neuroimaging traits with known links to reading and language.…”

“…Genetic variation explains a substantial component of reading abilities, with twin-based heritability (twin-h 2 ) estimates of 0.66 (Andreola et al, 2021) and population-based heritability (SNP-h 2 ) estimates of 0.50 (Verhoef et al, 2020). The largest genome-wide association study (GWAS) of language and reading-related traits to date (N~34,000) has confirmed the robust heritability estimates for these traits, identifying a single genome-wide significant locus for word reading in chromosome 1 (Eising et al, 2021). This study has also highlighted a shared genetic component of reading-related measures with other cognitive components and the cortical surface area (CSA) of the banks of the left superior temporal sulcus (STS; Eising et al, 2021).…”

“…The largest genome-wide association study (GWAS) of language and reading-related traits to date (N~34,000) has confirmed the robust heritability estimates for these traits, identifying a single genome-wide significant locus for word reading in chromosome 1 (Eising et al, 2021). This study has also highlighted a shared genetic component of reading-related measures with other cognitive components and the cortical surface area (CSA) of the banks of the left superior temporal sulcus (STS; Eising et al, 2021). Dyslexia also has a complex genetic and environmental aetiology, with twin-h 2 estimates of 0.40-0.60 (Fisher & DeFries, 2002) and SNP-h 2 estimates of 0.15-0.19 (Doust et al, 2021; Gialluisi et al, 2020).…”

“…Functional studies so far have relied on small samples (range: 33-427 participants; Landi & Perdue, 2019) and have shown mixed findings, reflecting the challenging task of characterizing the reading phenotype and combining it with informative task designs, as well as the difficulty to transfer those functional designs into larger datasets. Although structural imaging phenotypes have been studied in slightly larger sample sizes (range: 56-1,717; Landi & Perdue, 2019), these are still far from the sample sizes required to identify robust associations given the small genetic effects that are expected, given the polygenicity of both reading (Eising et al, 2021) and brain phenotypes (Smith et al, 2021). Hence, these studies provide a groundwork to understand the link from genetic variation to brain phenotypes and reading, but systematicity in the analytical approaches is lacking as, until now, only a handful of phenotypes and genetic loci have been considered.…”

Test of Prosody via Syllable Emphasis (“TOPsy”): Psychometric Validation of a Brief Scalable Test of Lexical Stress Perception

“…The goal of extending these lines of research to other speech, language, and reading traits highlights the need for coordinated efforts toward collecting and meta-analyzing large-scale data in cohorts that have been able to link language-related traits to genotypes. [e.g., GenLang consortium ( genlang.org ): Eising et al, 2021 , BioRXiv , Lancaster et al, in prep. ; International Stuttering Project ( theinternationalstutteringproject.com ): Polikowsky et al, 2021 ; Shaw et al, 2021 ].…”