Multivariate genome-wide association study of rapid automatized naming and rapid alternating stimulus in Hispanic and African American youth
Authors: Truong Dongnhu T. , Adams Andrew K. , Boada Richard , Frijters Jan C. , Hill Dina , Lovett Maureen W. , Mahone Mark E. , Willcutt Eric G. , Wolf Maryanne ,   Pediatric, Imaging, Neurocognition, and Genetics Consortium, Defries John C. , Gialluisi Alessandro , Francks Clyde , Fisher Simon E. , Olson Richard K. , Pennington Bruce F. , Smith Shelley D. , Bosson-Heenan Joan , Gruen Jeffrey R. 
Published: October 2017

Reading disability is a complex neurodevelopmental disorder that is characterized by difficulties in reading despite educational opportunity and normal intelligence. Performance on rapid automatized naming (RAN) and rapid alternating stimulus (RAS) tests gives a reliable predictor of reading outcome. These tasks involve the integration of different neural and cognitive processes required in a mature reading brain. Most studies examining the genetic factors that contribute to RAN and RAS performance have focused on pedigree-based analyses in samples of European descent, with limited representation of groups with Hispanic or African ancestry. In the present study, we conducted a multivariate genome-wide association analysis to identify shared genetic factors that contribute to performance across RAN Objects, RAN Letters, and RAS Letters/Numbers in a sample of Hispanic and African American youth (n=1,331). We then tested whether these factors also contribute to variance in reading fluency and word reading. Genome-wide significant, pleiotropic, effects across RAN Objects, RAN Letters, and RAS Letters/Numbers were observed for SNPs located on chromosome 10q23.31 (rs1555839, multivariate association, p=2.23 × 10−8), which also showed significant association with reading fluency and word reading performance (p <0.001). Bioinformatic analysis of this region using epigenetic data from the NIH Roadmap Epigenomics Mapping Consortium indicates active transcription of the geneRNLSin the brain. Neuroimaging genetic analysis of fourteen cortical regions in an independent sample of typically developing children across multiple ethnicities (n=690) showed that rs1555839 was associated with variation in volume of the right inferior parietal cortex—a region of the brain that processes numerical information and has been implicated in reading disability. This study provides support for a novel locus on chromosome 10q23.31 associated with RAN, RAS, and reading-related performance.

AUTHOR SUMMARY

Reading disability has a strong genetic component that is explained by multiple genes and genetic factors. The complex genetic architecture along with diverse cognitive impairments associated with reading disability, poses challenges in identifying novel genes and variants that confer risk. One method to begin parsing genetic and neurobiological mechanisms that contribute to reading disability is to take advantage of the high correlation among reading-related cognitive traits like rapid automatized naming (RAN) and rapid alternating stimulus (RAS) to identify shared genetic factors that contribute to common biological mechanisms. In the present study, we used a multivariate genome-wide analysis approach that identified a region of chromosome 10q23.31 associated with variation in RAN Objects, RAN Letters, and RAS Letters/Numbers performance in a sample of 1,331 Hispanic and African American youth in the Genes, Reading, and Dyslexia (GRaD) Study. Genetic variants in this region were also associated with reading fluency in GRaD, and differences in brain structures implicated in reading disability in a separate sample of 690 children. The gene,RNLS, is located within the implicated region of chromosome 10q23.31 and plays a role in breaking down a class of chemical messengers known to affect attention, learning, and memory in the brain. These findings provide a basis to inform our understanding of the biological basis of reading disability.