Journal
PLOS GENETICS
Volume 9, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003751
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Funding
- University of St Andrews
- UK Medical Research Council [G0800523/86473]
- Max Plank Society
- EU [018696, 241995]
- Wellcome Trust [090532/Z/09/Z, WT075491, WT090532, WT098017, WT083431MA]
- Medical Research Council Hub Grant [G0900747 91070]
- UK Medical Research Funding
- Nuffield Department of Medicine Prize Studentship
- MRC [MC_UP_A320_1004, G0800523, MC_UU_12021/4, MC_UU_12013/1, MC_UU_12013/4] Funding Source: UKRI
- Medical Research Council [G0800523, MC_UU_12013/4, MC_UP_A320_1004, G9815508, MC_UU_12021/4, MC_UU_12013/1] Funding Source: researchfish
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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 = 8.68x10(-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 overrepresentation (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.
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