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Dyslexia GWAS Leads to Dozens of Risk Loci, Polygenic Risk Score

NEW YORK – An international team led by investigators at the University of Edinburgh has identified dozens of new and known genetic risk loci for dyslexia, a neurodevelopmental condition marked by reading and other decoding difficulties.

The findings, appearing in Nature Genetics on Thursday, argued against genetic overlap between dyslexia and specific brain structure or subcortical volume changes, while highlighting genetic ties between dyslexia, ambidexterity, and performance on spelling or reading tests.

"Our results also suggest that dyslexia is very closely genetically related to performance on reading and spelling tests, reinforcing the importance of standardized testing in identifying dyslexia," co-senior and corresponding author Michelle Luciano, a researcher at the University of Edinburgh, said in a statement.

With a genome-wide association study that included 51,800 adults with self-reported dyslexia and nearly 1.1 million unaffected controls enrolled in 23andMe's research program, the researchers tracked down genetic associations in and around 15 genes previously implicated in educational attainment or cognitive ability, along with 27 genes that had not been linked to dyslexia or related traits in the past.

"Identifying genetic risk factors not only aids increased understanding of the biological mechanisms, but may also expand diagnostic capabilities, facilitating earlier identification of individuals prone to dyslexia and co-occurring disorders for specific support," the authors explained.

After bringing in additional genetic data for tens of thousands more dyslexia cases or controls, including individuals of Chinese or European ancestry from the GenLang Consortium, Chinese Reading Study, and NeuroDys cohorts, the team confirmed associations at 13 new and 10 known genetic loci, including variants in gene enhancer or promoter regions.

Along with age- and sex-specific association analyses that largely tracked with the broader GWAS findings, the investigators considered gene-level associations, risk variant-related expression quantitative trait loci, and related gene expression patterns, highlighting 20 genes from the gene-based analysis that appeared to be expressed at particularly high levels in brain tissue.

The team's correlation analyses pointed to genetic overlap with dozens of other traits, including attention-deficit hyperactivity disorder, ambidextrous handedness, or performance on reading or spelling tests — results backed up by subsequent polygenic risk score (PRS) modeling. For example, individuals with the top scores on a dyslexia PGS established with GWAS data tended to coincide with poorer reading or spelling skills in thousands of adolescent or adult participants from four more population cohorts.

"Dyslexia polygenic scores were correlated with lower achievement on reading and spelling tests in population-based and reading-disorder enriched samples, especially for nonword reading, a measure of phonological decoding that is typically impaired in dyslexia," the authors reported, noting that dyslexia PRSs "could become a valuable tool to help identify children with a propensity for dyslexia, enabling learning support before development of reading skills."