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

William M. Brandler; Andrew P. Morris; David M. Evans; Thomas S. Scerri; John P. Kemp; Nicholas J. Timpson; Beate St Pourcain; George D. Smith; Susan M. Ring; John Stein; Anthony P. Monaco; Joel B. Talcott; Simon E. Fisher; Caleb Webber; Silvia Paracchini

doi:10.1371/journal.pgen.1003751

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

William M. Brandler, Andrew P. Morris, David M. Evans, Thomas S. Scerri, John P. Kemp, Nicholas J. Timpson, Beate St Pourcain, George D. Smith, Susan M. Ring, John Stein, Anthony P. Monaco, Joel B. Talcott, Simon E. Fisher, Caleb Webber^*, Silvia Paracchini

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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. © 2013 Brandler et al.

Original language	English
Article number	e1003751
Number of pages	11
Journal	PLoS Genetics
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1003751
Publication status	Published - Sept 2013

Bibliographical note

This work was supported by the University of St Andrews, the UK Medical Research Council (grant number G0800523/86473 to SP), the Max Plank Society, and the the EU (Neurodys, 018696). Genotyping at the Wellcome Trust Centre for Human Genetics was supported by the Wellcome Trust (090532/Z/09/Z) and a Medical Research Council Hub Grant (G0900747 91070). Core support for ALSPAC was provided by the UK Medical Research Council and the Wellcome Trust (092731) and the University of Bristol. SP is a Royal Society University Research Fellow. CW is also funded by the UK Medical Research Funding and the EU (GENCODYS, 241995). APMor was supported by the Wellcome Trust (grant numbers WT075491, WT090532, and WT098017). WMB is the recipient of a Nuffield Department of Medicine Prize Studentship. JPK is funded by a Wellcome Trust PhD studentship (WT083431MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2013 Brandler et al. 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 credited.

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10.1371/journal.pgen.1003751

Common variants in left-right asymmetry genes
Copyright: © 2013 Brandler et al. 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 credited.
Final published version, 409 KBLicence: CC BY 3.0

http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003751

Cite this

Brandler, W. M., Morris, A. P., Evans, D. M., Scerri, T. S., Kemp, J. P., Timpson, N. J., St Pourcain, B., Smith, G. D., Ring, S. M., Stein, J., Monaco, A. P., Talcott, J. B., Fisher, S. E., Webber, C., & Paracchini, S. (2013). Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genetics, 9(9), Article e1003751. https://doi.org/10.1371/journal.pgen.1003751

@article{065562af4eb44a64bd14013fc0079220,

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

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. {\textcopyright} 2013 Brandler et al.",

author = "Brandler, {William M.} and Morris, {Andrew P.} and Evans, {David M.} and Scerri, {Thomas S.} and Kemp, {John P.} and Timpson, {Nicholas J.} and {St Pourcain}, Beate and Smith, {George D.} and Ring, {Susan M.} and John Stein and Monaco, {Anthony P.} and Talcott, {Joel B.} and Fisher, {Simon E.} and Caleb Webber and Silvia Paracchini",

note = "This work was supported by the University of St Andrews, the UK Medical Research Council (grant number G0800523/86473 to SP), the Max Plank Society, and the the EU (Neurodys, 018696). Genotyping at the Wellcome Trust Centre for Human Genetics was supported by the Wellcome Trust (090532/Z/09/Z) and a Medical Research Council Hub Grant (G0900747 91070). Core support for ALSPAC was provided by the UK Medical Research Council and the Wellcome Trust (092731) and the University of Bristol. SP is a Royal Society University Research Fellow. CW is also funded by the UK Medical Research Funding and the EU (GENCODYS, 241995). APMor was supported by the Wellcome Trust (grant numbers WT075491, WT090532, and WT098017). WMB is the recipient of a Nuffield Department of Medicine Prize Studentship. JPK is funded by a Wellcome Trust PhD studentship (WT083431MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: {\textcopyright} 2013 Brandler et al. 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 credited.",

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Brandler, WM, Morris, AP, Evans, DM, Scerri, TS, Kemp, JP, Timpson, NJ, St Pourcain, B, Smith, GD, Ring, SM, Stein, J, Monaco, AP, Talcott, JB, Fisher, SE, Webber, C & Paracchini, S 2013, 'Common variants in left/right asymmetry genes and pathways are associated with relative hand skill', PLoS Genetics, vol. 9, no. 9, e1003751. https://doi.org/10.1371/journal.pgen.1003751

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AU - Brandler, William M.

AU - Morris, Andrew P.

AU - Evans, David M.

AU - Scerri, Thomas S.

AU - Kemp, John P.

AU - Timpson, Nicholas J.

AU - St Pourcain, Beate

AU - Smith, George D.

AU - Ring, Susan M.

AU - Stein, John

AU - Monaco, Anthony P.

AU - Talcott, Joel B.

AU - Fisher, Simon E.

AU - Webber, Caleb

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N2 - 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. © 2013 Brandler et al.

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

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