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.

On the other hand: including left-handers in cognitive neuroscience and neurogenetics

“…PCSK6 encodes a protease enzyme that cleaves Nodal, a protein that has a role in the regulation of the left-right visceral axis (of the heart, lungs, and so on) in early embryogenesis 127 . GWAS analysis of this same dataset, in combination with data from other cohorts, has provided evidence that additional genes involved in left-right visceral patterning are associated with relative hand skill 129 . These studies provide a hint that human handedness and visceral asymmetries may be genetically connected, at least to some extent.…”

The Many Sides of Hemispheric Asymmetry: A Selective Review and Outlook

“…Another large-scale study also showed no effect of this allele in the general population, but revealed that a repeat polymorphism at another locus was associated with the degree, but not the direction, of handedness (Arning et al, 2013), and this same repeat has also been associated with attention deficit hyperactivity disorder (ADHD) (Kebir & Joober, 2011). Shore et al (2016) demonstrated an effects on gene expression regulation for the associated SNP but not the repeat polymorphism Several other genes in the pathway that leads to anomalies of left-right development in mice proved to be associated as a group with human handedness in the general population (Brandler et al, 2013). Integrating these and other findings, Brandler and Paracchini (2014) appeal to the cilia themselves, arguably the very source of bodily asymmetries.…”

Medea Genes, Handedness and Other Traits

“…Asymmetry in brain lateralization is a common trait among vertebrates, including mammals [3].Cerebral asymmetries are well documented in humans; in particular, handedness preference (i.e., right handed or non-right handed) and in the language-related areas of the brain (i.e., cerebral or speech laterality, right-brained or leftbrained language dominance) [4]. Amar Klar [5] argued that the gene that determines handedness in humans is related to hair-whorl rotation (i.e., the direction the hair spins at the back of the head, either clockwise or counterclockwise), although this gene remains to be identified.…”