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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doaj-fbe4eda1f16d4344b02f6b5f40dd27df2020-11-25T00:53:56ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-0199e100375110.1371/journal.pgen.1003751Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.William M BrandlerAndrew P MorrisDavid M EvansThomas S ScerriJohn P KempNicholas J TimpsonBeate St PourcainGeorge Davey SmithSusan M RingJohn SteinAnthony P MonacoJoel B TalcottSimon E FisherCaleb WebberSilvia ParacchiniHumans 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.http://europepmc.org/articles/PMC3772043?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
William M Brandler Andrew P Morris David M Evans Thomas S Scerri John P Kemp Nicholas J Timpson Beate St Pourcain George Davey Smith Susan M Ring John Stein Anthony P Monaco Joel B Talcott Simon E Fisher Caleb Webber Silvia Paracchini |
spellingShingle |
William M Brandler Andrew P Morris David M Evans Thomas S Scerri John P Kemp Nicholas J Timpson Beate St Pourcain George Davey Smith Susan M Ring John Stein Anthony P Monaco Joel B Talcott Simon E Fisher Caleb Webber Silvia Paracchini Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genetics |
author_facet |
William M Brandler Andrew P Morris David M Evans Thomas S Scerri John P Kemp Nicholas J Timpson Beate St Pourcain George Davey Smith Susan M Ring John Stein Anthony P Monaco Joel B Talcott Simon E Fisher Caleb Webber Silvia Paracchini |
author_sort |
William M Brandler |
title |
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_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_sort |
common variants in left/right asymmetry genes and pathways are associated with relative hand skill. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2013-01-01 |
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. |
url |
http://europepmc.org/articles/PMC3772043?pdf=render |
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