Towards disentangling the polygenic contribution of dyslexia to school performance.

Dyslexia is a neurodevelopmental disorder typically diagnosed in school-aged children and associated with poor school performance and lower levels of educational attainment (EA). Here, we aimed to test the shared genetic architecture between dyslexia and EA, to dissect the polygenic contribution of dyslexia by its relationship with EA and to assess how these genetic partitions influence school performance, early manifestation of psychopathology and related traits. We first confirmed a negative genetic correlation between dyslexia and EA (rg = -0.186, SE = 0.019, P = 1.75E-22). Then, polygenic scores for EA and dyslexia were tested in a cohort of 4274 school-aged children, revealing opposite direction of the effect in school performance. Next, we dissected the genetic liability for dyslexia into components shared with, and independent of, EA. The results revealed similar patterns of association for performance in primary and foreign languages, but distinct patterns when comparing these language-related subjects with mathematics. The dyslexia-specific genetic component independent of EA was associated with poorer academic outcomes in language-related subjects and increased rates of psychopathology, supporting the existence of dyslexia-specific genetic effects beyond general cognitive or educational pathways. In contrast, the genetic load of dyslexia that overlaps with EA contributes to school performance in both language-related subjects and mathematics and displayed opposite patterns of association dependent on whether concordant and discordant genomic partitions were considered. The discordant partition was associated with poorer school performance and higher rates of behavioral and emotional problems, with these associations being partially mediated by the dyslexia diagnosis (accounting for a reduction in effect size ranging from 10.44-12.91%). Conversely, the concordant partition was only associated with better performance in mathematics. Overall, these findings highlight the polygenic contribution of dyslexia to both academic and psychopathological outcomes, support distinct genetic influences on language skills and mathematics, and underscore the usage of the genetic load for EA to deepen insight into the complex genetic relationship between dyslexia and school performance.