PLoS Genetics (Jan 2013)

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 Davey Smith,
  • Susan M Ring,
  • John Stein,
  • Anthony P Monaco,
  • Joel B Talcott,
  • Simon E Fisher,
  • Caleb Webber,
  • Silvia Paracchini

DOI
https://doi.org/10.1371/journal.pgen.1003751
Journal volume & issue
Vol. 9, no. 9
p. e1003751

Abstract

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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.