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Handedness GWAS Leads to Suspected Left-Right Asymmetry Genes

NEW YORK (GenomeWeb News) – A team from the UK and the Netherlands has garnered evidence suggesting left- and right-handedness may involve genes from some of the same pathways that produce other features differing on right and left sides of the body.

As they reported in PLOS Genetics last night, researchers from the University of Oxford, the University of St. Andrews, and elsewhere began by doing a genome-wide association study meta-analysis involving thousands of individuals with or without dyslexia whose right- and left-handed skills had been tested for past studies.

In those with dyslexia — a reading disability in which shifts in left-right symmetry has been described in certain brain regions — the SNP most significantly linked to handedness fell in an enzyme-coding gene implicated in the development of left-right asymmetry in several animal species.

Through a gene-set enrichment analysis, meanwhile, the team saw an over-representation of potential handedness contributors in genes corresponding to mouse pathways tied to left-right asymmetry. Similar sorts of genes may contribute to handedness in those without dyslexia too, the study suggests, but the specific genes and variants involved appear to be different.

Such differences may reflect potential epistatic interactions between dyslexia and handedness, study authors noted, as well as other genetic and environmental factors contributing to the trait.

"As with all aspects of human behavior, nature and nurture go hand-in-hand," first author William Brandler, a graduate student affiliated with the University of Oxford's MRC functional genomics unit and the Wellcome Trust Centre for Human Genetics, said in a statement. "The development of handedness derives from a mixture of genes, environment, and cultural pressure to conform to right-handedness."

Some 85 percent or more of humans are biased towards using tools with their right hand rather than their left, Brandler and his colleagues noted, though that handedness asymmetry has not been detected in other branches of the great ape tree.

Prior studies have hinted that handedness has its roots in asymmetrical parts of the brain involved in movement, language, and the like. On the other hand, subtle changes to these and other regions of the brain with physical or functional sidedness have been suspected of contributing to some neurodevelopmental conditions.

Some members of the same research team took advantage of the latter relationship for a GWAS of handedness appearing in Human Molecular Genetics in 2011 by focusing on individuals with dyslexia. That study unearthed an association between handedness and a SNP called 11855415 in PCSK6, a protease enzyme gene proposed to play a role in the establishment of features with right-left asymmetry in a range of species.

Another variant in the same PCSK6 gene turned up as the top hit in researchers' current search for SNPs associated with handedness, too, again amongst individuals with dyslexia.

The meta-analysis hinged on genotyping profiles for 728 individuals with dyslexia or other forms of reading disorder from four past studies, along with 2,666 unaffected individuals from the same population. Participants' left-right hand preferences and dexterity had been determined with the help of a pegboard test for hand skill.

To look for other genes that might contribute to handedness, the team turned to a gene-set enrichment analysis, which looked for an over-representation of handedness-associated variants across certain genes — particularly the human orthologous of genes described as having a role in left-right asymmetry in mice.

By using the Broad Institute's "Meta-analysis gene-set enrichment of variant associations," or MAGENTA, software to sort through the data, the researchers saw a higher-than-usual concentration of apparent handedness-associated variants in genes from four of the 15 pathways related to asymmetrical right-left features in the Mouse Genome Informatics database.

That over-representation was detected specifically in the individuals with dyslexia, researchers noted, though they saw a similar enrichment for possible handedness-linked variants across genes from three of the four asymmetry pathways in individuals without dyslexia or other forms of reading disorder.

"We propose that handedness is under the control of many variants," Brandler and his co-authors wrote, "some of which are genes that also contribute to the determination of body [left-right] symmetry."

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