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Dozens of Genetic Loci Influence Handedness, GWAS Meta-Analysis Finds

NEW YORK – More than 40 genetic loci may influence whether someone is left-handed, a new genome-wide association meta-analysis has found.

About 9 percent of the human population is left-handed, but what governs handedness is unclear.

Researchers led by the University of Queensland's Sarah Medland used data from the UK Biobank, 23andMe, and the International Handedness Consortium (IHC) to uncover loci associated with left-handedness as well as being ambidextrous. These loci implicated pathways involved in the regulation of microtubules and brain morphology in handedness. As they reported in their study, published Monday in Nature Human Behavior, the researchers also found correlations between left-handedness and neuropsychiatric conditions. However, there was only a low genetic correlation between left-handedness and ambidexterity, suggesting the two have different genetic influences.

"The 41 genetic variants influencing left-handedness were different to the seven we identified for ambidexterity, and we saw very little correlation between the results for the two traits," Medland said in a statement.

For their study, the researchers combined data from the UK Biobank, 23andMe, and IHC cohorts that included more than 1.5 million right-handed and about 194,200 left-handed individuals. In their analysis, they identified 41 loci associated with being left-handed that reached genome-wide significance. A phenome-wide association scan noted that 28 of the 41 lead SNPs have previously been tied to other complex traits, including schizophrenia.

A number of these loci, the researchers noted, are located near genes involved in microtubule formation or regulation. Additional pathway and tissue analyses using the MAGMA and DEPICT analysis tools further linked pathways involved in the regulation of microtubules to left-handedness and also implicated tissues of the central nervous system, particularly the hippocampus and cerebrum. Microtubule proteins, the researchers noted, have key roles in the development and migration of neurons, plasticity, and neurodegenerative processes, which could influence handedness.

A genetic correlation analysis between left-handedness and more than 1,300 other complex traits did not uncover significant association, but did suggest positive correlations between left-handedness and neurological and psychiatric conditions like schizophrenia, bipolar disorder, intracranial volume, and educational attainment.

Previously, twin studies have indicated that the heritability of left-handedness is about 25 percent. But in their analysis, the researchers estimated that the variance in handedness explained by SNPs is modest, about 3.5 percent. "The results from our analyses suggested that genetic factors could only account for a small amount of the variation in handedness, whereas environmental factors were likely to play a much more important role," co-senior author David Evans from the University of Queensland said in a statement.

The researchers also conducted a genome-wide association study of ambidexterity using UKBB and 23andMe data on 37,637 ambidextrous individuals and 1.4 million right-handed individuals. Through this, they linked seven loci to ambidexterity. Sixteen of the 41 SNPs linked to left-handedness were nominally associated with ambidexterity.

While a DEPICT analysis did not implicate any tissue or pathway in ambidexterity, a MAGMA-based analysis highlighted a number of brain tissues, including the cerebellum and pathways such as those regulating cell size, basal dendrites, and postsynaptic cytosol, as involved in being ambidextrous. 

Through a genetic correlation analysis, they noted correlations between ambidexterity and traits linked to pain and injury. In addition, the genetic correlation between ambidexterity and left-handedness was moderate, indicating the two have different genetic origins.

These findings, the researchers noted, suggest that handedness, similar to other complex traits, is affected by a number of variants, each with a small effect, and numerous biological pathways.