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Common variants in left/right asymmetry genes and pathways are associated with relative hand skill

Brandler, William M., Morris, Andrew P., Evans, David M., Scerri, Thomas S., Kemp, John P., Timpson, Nicholas J., St Pourcain, Beate, Smith, George Davey, Ring, Susan M., Stein, John, Monaco, Anthony P., Talcott, Joel B., Fisher, Simon E., Webber, Caleb ORCID: https://orcid.org/0000-0001-8063-7674 and Paracchini, Silvia 2013. Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genetics 9 (9) , e1003751. 10.1371/journal.pgen.1003751

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Public Library of Science
ISSN: 1553-7390
Date of First Compliant Deposit: 22 October 2020
Date of Acceptance: 10 July 2013
Last Modified: 07 May 2023 19:35
URI: https://orca.cardiff.ac.uk/id/eprint/135769

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