Frijters, J. C. | Search bioRxiv

bioRxiv2021

Genome Wide Association Study in the New Haven Lexinome Project Identifies GARRE1 as a Novel Gene for Reading Performance

Despite high prevalence and high heritability, few candidate genes have been identified for reading disability. To identify novel genetic variants we performed a genome-wide association study (GWAS) using high-depth whole genome sequencing and predicated on reading performance in 407 subjects enrolled in a longitudinal study of response-to-intervention, called the New Haven Lexinome Project. The primary GWAS identified a single peak of 31 SNPs on chromosome 19 that achieved the threshold for genome-wide significance (rs2599553 P=3.13x10-8) located over an expression quantitative trait locus (eQTL) for GARRE1 (Granule Associated Rac And RHOG Effector 1). Little is known about the function of GARRE1, except that it is highly and developmentally expressed in human cerebellum relative to cortex. Local ancestry regression showed the strongest association for the lead variant in African or Admixed American populations, who have been under-represented in previous genetic studies of reading. We replicated our chromosome 19 results in the Genes, Reading, and Dyslexia (GRaD) cohort and found a moderating effect of age with implications for the consideration of developmental effects in the design of future analyses. Growth curve modeling demonstrated that minor alleles of the lead SNP are related to reading longitudinally from Grade 1 to Grade 5, and that children with at least 1 minor allele of rs2599553 persistently underperformed relative to their peers by 0.33 to 0.5 standard deviations on standardized assessments of non-word decoding and reading fluency. Significance StatementTo the best of our knowledge, this work represents the only GWAS predicated on longitudinal reading performance data. Starting with initial discovery, we replicate our association in a second cohort, address common causes of type I error, localize the signal to a single gene, implicate a region of the brain most likely to be affected by variation in our candidate, show a gene-by-age effect with implications for study design in this field, and demonstrate that minor alleles of our lead SNP are associated with significant and persistent clinical effects on reading development in children.

genetics↗

bioRxiv2017

Multivariate genome-wide association study of rapid automatized naming and rapid alternating stimulus in Hispanic and African American youth.

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 x 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 gene RNLS in 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.\n\nAUTHOR SUMMARYReading 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.

genetics↗