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

Research output: Contribution to journalArticle (Academic Journal)peer-review

116 Citations (Scopus)


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.

Original languageEnglish
Article number1003751
Pages (from-to)e1003751
Number of pages11
JournalPLoS Genetics
Issue number9
Publication statusPublished - Sept 2013


  • Animals
  • Body Patterning
  • Brain
  • Dyslexia
  • Functional Laterality
  • Genome-Wide Association Study
  • Humans
  • Mice
  • Multifactorial Inheritance
  • Proprotein Convertases
  • Serine Endopeptidases


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