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- Title
Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill.
- Authors
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
- 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.
- Subjects
BRAIN; META-analysis; GENOMES; DYSLEXIA; LOCUS (Genetics)
- Publication
PLoS Genetics, 2013, Vol 9, Issue 9, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1003751