Skip to main content
Premium Trial:

Request an Annual Quote

Rare Genetic Contributors to Left-Handedness Uncovered Using UK Biobank Exomes

Left Handed Writing

NEW YORK – A rare variant analysis focused on protein-coding parts of the genome has identified apparent contributors to left-handedness in humans, highlighting a role for microtubule-related tubulin genes involved in cytoskeletal functions in cells.

As they reported in Nature Communications on Tuesday, researchers at the Max Planck Institute for Psycholinguistics in the Netherlands and Radboud University turned to available exome sequencing profiles to search for rare variants linked to left-handedness in hundreds of thousands of middle-aged or older UK Biobank participants, including 313,271 right-handers and 38,043 individuals who are left-handed.

"In our new study we looked instead at rarer genetic variants which affect protein sequences," senior and corresponding author Clyde Francks, neurobiologist with the Max Planck Institute for Psycholinguistics in the Netherlands, said in an email. "These types of genetic variants can have much larger effects on human traits in the few people who carry them."

Along with a meta-analysis of all participants, the team searched for genetic factors linked to left-handedness within distinct ancestry groups, since rates of self-reported left-handedness vary between individuals from different populations.

For example, Francks noted that rates of documented left-handedness tend to be lower in individuals from Africa, Asia, and the Middle East than they are in North America or Europe — a pattern that may be partly explained by suppression of left-handedness in certain cultures.

Roughly one in 10 individuals in the general population have a dominant right brain hemisphere, leading to left-handedness, the team explained. But while the trait is expected to be at least partially explained by genetics, past genome-wide association studies centered on common variants have left questions about the trait's biological basis.

"We know that the two cerebral hemispheres already start to develop differently in the human embryo, but the mechanism is not known," Francks explained. "Finding genes linked to asymmetries of the brain or behavior, like handedness, can give some clues."

Consistent with common genetic variants associated with left-handedness in prior GWAS, the researchers saw an overrepresentation of rare coding variants in the beta-tubulin-coding gene TUBB4B in left-handed UK Biobank participants.

"[T]his is a nice convergence of the evidence, although the exact genes implicated by the two approaches have been different," Francks explained, adding that rare TUBB4B coding variant turned up roughly two to three times more frequently in left-handed individuals.

The work suggests that microtubules may contribute to the establishment of left and right hemisphere asymmetry in the developing brain, he added, noting the team hopes to explore potential microtubule roles in embryonic brain development using mouse embryo models.

"[M]icrotubules might help to create the left-right axis by giving some cells an asymmetrical twist at a certain stage," Francks explained. "Alternatively, the microtubules within cilia might give rise to asymmetrical movements and fluid flows. Cilia are projections from the cell surface that are supported by microtubules."

Because left-handedness has been found at higher-than-usual levels in individuals diagnosed with conditions such as autism spectrum disorder (ASD) and schizophrenia, the team also searched for potential genetic overlap between genes impacted by rare variants in left-handed individuals and those implicated in ASD, schizophrenia, or Parkinson's disease.

"Left-handedness is more common in autism and schizophrenia than in the general population, so altered asymmetry of the brain arising from genetic variants might distinguish a subset of affected people," Francks said.

Though he cautioned that "most left-handed people do not have autism or schizophrenia," Francks noted that the associations hint at "links between the development of brain asymmetry and psychiatric traits."

In particular, the team's analyses pointed to potential left-handedness roles for rare coding variants in the nervous system development-related gene DSCAM and FOXP1, a transcription factor-coding gene. Alterations in DSCAM and FOXP1 have been linked to ASD or ASD-related symptoms, or development/speech changes, respectively.

Together, the rare protein-coding variants identified so far appeared to explain 0.91 percent of left-handedness heritability. That, in turn, suggested that rare coding variants "make only a very small contribution to the rate of left-handedness in the population as a whole," Francks explained, noting that prior development studies indicate that "brain asymmetry varies mostly due to randomness in the early embryo."

"For our purpose, the low heritability was not a problem," he said. "Rare genetic variants in just a handful of people can pinpoint genes that give clues to developmental mechanisms of brain asymmetry in everyone."