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

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.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Hand preference and Mathematical Learning Difficulties: New data from Greece, the United Kingdom, and Germany and two meta-analyses of the literature.

Increased rates of atypical handedness are observed in neurotypical individuals who are low-performing in mathematical tasks as well as in individuals with special educational needs, such as dyslexia. This is the first investigation of handedness in individuals with Mathematical Learning Difficulties (MLD). We report three new studies (N = 134; N = 1,893; N = 153) and two sets of meta-analyses (22 studies; N = 3,667). No difference in atypical hand preference between MLD and Typically Achieving (TA) individuals was found when handedness was assessed with self-report questionnaires, but weak evidence of a difference was found when writing hand was the handedness criterion in Study 1 (p = .049). Similarly, when combining data meta-analytically, no hand preference differences were detected. We suggest that: (i) potential handedness effects require larger samples, (ii) direction of hand preference is not a sensitive enough measure of handedness in this context, or that (iii) increased rates of atypical hand preference are not associated with MLD. The latter scenario would suggest that handedness is specifically linked to language-related conditions rather than conditions related to cognitive abilities at large. Future studies need to consider hand skill and degree of hand preference in MLD.

Genome-wide association study and polygenic risk score analysis for hearing measures in children.

An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HTs) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWASs) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by external environmental factors. Here, we investigated HT and HTA in a children population cohort (ALSPAC, n = 6,743). Better hearing was associated with better cognitive performance and higher socioeconomic status. At the group level, HTA suggested a left ear advantage (mean = -0.28 dB) that was mainly driven by females. SNP heritability for HT and HTA was 0.13 and 0.02, respectively (n = 4,989). We found a modest negative genetic correlation between HT and reading ability. GWAS for HT (n = 5,344) did not yield significant hits but polygenic risk scores for higher educational attainment (EA, ß = -1,564.72, p = .008) and schizophrenia (ß = -241.14, p = .004) were associated with lower HT, that is, better hearing. In summary, we report new data supporting associations between hearing measures and cognitive abilities at the behavioral level. Genetic analysis suggests shared biological pathways between cognitive and sensory systems and provides evidence for a positive outcome of genetic risk for schizophrenia.

A GWAS for grip strength in cohorts of children-Advantages of analysing young participants for this trait.

Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genome-wide association studies (GWASs) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta-analyses on maximal GS with the dominant (GSD) and non-dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5450; age range = 10.65-13.61; Raine Study, N = 1162, age range: 9.42-12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e-08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an expression quantitative trait locus (eQTL) effect. Despite a much smaller sample (~3%) compared with the UK Biobank we replicated correlation analyses previously reported in this much larger adult cohort, such as a negative correlation with coronary artery disease. Although the results from the polygenic risk score (PRS) analyses did not survive multiple testing correction, we observed nominally significant associations between GS and risk of overall fracture, as previously reported, as well ADHD which will require further investigations. Finally, we observed a higher SNP-heritability (24%-41%) compared with previous studies (4%-24%) in adults. Overall, our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared with adults.

Identification of loci involved in childhood visual acuity and associations with cognitive skills and educational attainment.

Visual acuity significantly contributes to quality of life. Deficits in childhood are associated with reading difficulties, which can have detrimental effects on education outcomes. In adults, it has been observed that vision defects such as myopia are associated with higher educational attainment (EA). Understanding genetic factors contributing to visual acuity could help to dissect its links with cognitive skills, neurodevelopmental conditions, and education. We examined associations between distance visual acuity, cognitive measures including school grades, and neurodevelopmental conditions in a longitudinal cohort of British children (ALSPAC, n = 6807, M age = 11.8). We performed a genome-wide association study (GWAS, n = 5571) on visual acuity and tested for genetic associations with relevant phenotypes using polygenic scores (PGS) and genetic correlation analyses. Visual acuity was associated with better cognitive performance and school grades, and reduced in individuals with reading difficulties compared to controls. GWAS revealed genetic associations at the NPLOC4 locus and highlighted other genes involved in sensory function. In line with positive genetic correlations between visual acuity and cognitive measures, EA PGS were positively associated with visual acuity, while there was a less robust negative association with myopia PGS. In conclusion, increased visual acuity is associated with a range of positive outcomes, including better school grades. Our results suggest an association between a higher EA PGS and slightly increased visual acuity in childhood. This could indicate gene-environment correlation, in which environmental exposures linked to higher EA might have detrimental effects on vision offsetting the initial positive effect.