Mediational effects of reading-related intermediate phenotypes from polygenic scores to reading skills

Reading is a fundamental human capacity that recruits and tunes brain circuitry subserving several neurocognitive skills. Individual differences in reading-related skills are largely influenced by genetic variation. However, the molecular basis of the heritability of reading-related skills remains narrowly replicated. Genome-wide association studies have enabled the computation of cumulative indices (polygenic scores-PGSs) aiming to capture individuals' genetic susceptibility for a given trait. By using a multiple-mediator framework, we investigated whether the associations between a reading-specific PGS (Reading-PGS) and reading decoding and comprehension could be explained by reading-related endophenotypes (i.e., phonological awareness-PA, phonological memory, rapid auditory processing, rapid bimodal temporal processing-RBTP, and rapid automatized naming) in a sample of 8-year-old French-speaking Canadian twins (N = 328 subjects (87 MZ and 241 DZ) from 208 twin pairs-one child per MZ pairs; males, N = 159). The association between Reading-PGS and reading performance is partially mediated by PA and RBTP. Furthermore, we supported the specificity of the direct and indirect effects between Reading-PGS and reading skills after controlling for the shared genetic variation with educational attainment and cognitive ability. Finally, we uncovered a sequence from Reading-PGS to behavior mediated through sensory processing and phonological skills, supporting one of the most robust theoretical hypothesis underlying reading acquisitions. PGSs specifically targeting reading skills are essential for improved prediction and understanding of the complex etiology through which reading skills unfold during childhood. This will facilitate the early identification of children with a genetic susceptibility for reading (dis)ability at a time when these phenotypes remain malleable to intervention.