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Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill

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 individual...

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Autores principales: 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, Paracchini, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772043/
https://www.ncbi.nlm.nih.gov/pubmed/24068947
http://dx.doi.org/10.1371/journal.pgen.1003751
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author 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
Paracchini, Silvia
author_facet 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
Paracchini, Silvia
author_sort Brandler, William M.
collection PubMed
description 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.
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spelling pubmed-37720432013-09-25 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 Paracchini, Silvia PLoS Genet Research Article 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. Public Library of Science 2013-09-12 /pmc/articles/PMC3772043/ /pubmed/24068947 http://dx.doi.org/10.1371/journal.pgen.1003751 Text en © 2013 Brandler et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
Paracchini, Silvia
Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
title Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
title_full Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
title_fullStr Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
title_full_unstemmed Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
title_short Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill
title_sort common variants in left/right asymmetry genes and pathways are associated with relative hand skill
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772043/
https://www.ncbi.nlm.nih.gov/pubmed/24068947
http://dx.doi.org/10.1371/journal.pgen.1003751
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