Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
Year: 2013
Type: review
Study design: Observational Study
Abstract: Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Source: PLoS Genetics
Institutions: Centre for Human Genetics, University of Oxford, University of Bristol, Walter and Eliza Hall Institute of Medical Research, Aston University, Radboud University Nijmegen, Max Planck Institute for Psycholinguistics, Donders Institute for Brain, Cognition and Behaviour, University of St Andrews
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: G1681111766, G1849559488, G2050123317, Statistical methods for the analysis of genome-wide association and re-sequencing studies., G2615352456, G3030009606, G3445609543, G3573311078, Identification and functional analysis of susceptibility genes in multifactorial disease., G3761937116, G4182683118, The Avon Longitudinal Study of Parents and Children: An international resource for population genomics and lifecourse epidemiology. Core Programme Support 2011-2013., G5605389433, G582688034, G5846212695, G6133016579, G6737906592, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8975541179, G9000309734
OpenAlex ID: W2145827570