Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms.
Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach.
Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted.
Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule.
Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.
- complex traits
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Contributors DTT designed the experiments, performed statistical analyses and wrote the manuscript. AKA and SP provided computational and bioinformatic support and edited the manuscript. JCF performed statistical analyses and edited the manuscript. RB, DEH, MWL, EMM, EGW, MW, JCD, AG, CF, SEF, RKO, BFP, SDS and JB-H collected data and edited the manuscript. JRG obtained funding for the GRaD study, collected data and edited the manuscript.
Funding The Genes, Reading, and Dyslexia study was funded by The Manton Foundation (JRG, JCF, JB-H, DTT). The Colorado Learning Disabilities Cohort was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Grant (P50HD027802; JRG, JCD, RKO, BFP, SDS, EGW). The Pediatric Imaging, Neurocognition, and Genetics study was funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (RC2DA029475). DTT was funded by the Lambert Family and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD07094 and K99HD094902). AKA was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007149). The Max Planck Society supported AG, CF and SEF, and funded the genetic analyses of the CLDRC cohort. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Summary statistics will be made available through the NHGRI-EBI GWAS Catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics
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