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.

Figure 1. PCSK6 is associated with relative hand skill in individuals with reading disability.

Manhattan plot and visualization of P-values at the PCSK6 locus. (A) Manhattan plot of the P values for the meta-analysis of the RD Peg relative hand skill GWAS data-sets (cohorts 1–3). The observed P values are plotted against chromosome and position along the genome. The green dots represent markers that are genome-wide significant at P≤5×10⁻⁸. (B) Negative log₁₀ of the P-values for all genotyped and imputed SNPs around PCSK6 plotted in LocusZoom. Linkage disequilibrium (r²) with the most highly associated SNP, rs7182874 (purple diamond), is shown by the color of the SNPs. The recombination rate is shown by the blue line and the locations of genes in this locus are shown in the panel below the plot.