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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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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. |
format | Online Article Text |
id | pubmed-3772043 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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