Summary: A large-scale analysis of UK Biobank exome data has identified rare protein-altering variants associated with left-handedness, most notably in the beta-tubulin gene TUBB4B. These results strengthen the link between microtubule-related genes and brain asymmetry and reveal genetic overlap between handedness and certain neurodevelopmental disorders.
Using exome sequences from hundreds of thousands of participants, researchers have located uncommon coding changes that occur more frequently in people who are left-handed. While the effect sizes are clear for some rare variants, they explain only a small portion of handedness heritability, indicating that handedness arises from a complex mix of genetic, developmental, and environmental influences.
Key Facts:
- Rare coding variants in the TUBB4B gene are significantly enriched in left-handed individuals, providing direct evidence for a genetic component to handedness.
- Some rare variants associated with left-handedness are located in genes previously implicated in neurodevelopmental disorders—examples include DSCAM and FOXP1—highlighting shared biological pathways.
- Despite these discoveries, rare coding variants account for only about 0.9–1.0% of the exome-wide heritability of left-handedness, underscoring the multifactorial nature of the trait.
Background and significance
Handedness reflects the brain’s left-right functional specialization. Approximately 90% of people are right-handed, and the remaining population shows varying degrees of left-handedness. Studying handedness can reveal important information about brain development and organization, and its links to cognition and neurodevelopmental conditions.
Previous genome-wide association studies (GWAS) implicated many common, non-coding variants that likely affect gene regulation. This new exome-wide study complements those findings by focusing on rare, protein-altering variants—changes that directly affect amino acid sequences and can provide stronger clues about biological mechanisms.
What the study found
Researchers examined exome data from 38,043 left-handed and 313,271 right-handed UK Biobank participants to test whether rare coding variants (frequency ≤ 1%) are associated with handedness. The most striking result was an exome-wide significant excess of rare coding variants in the TUBB4B gene among left-handed individuals. Overall, rare TUBB4B variants were about 2.7 times more common in left-handers than right-handers.
Most of the TUBB4B changes were heterozygous missense variants—single amino-acid substitutions—though two unique frameshift mutations were observed only in left-handed participants. While other TUBB4B variants have previously been linked to sensorineural or ciliopathic conditions, the specific variants identified in this analysis are distinct and point to new functional questions about microtubule biology in brain development.
Beyond TUBB4B, the study detected associations between left-handedness and rare coding variants in genes already implicated by exome screening for autism and schizophrenia, including DSCAM and FOXP1. These overlaps suggest that some of the molecular pathways influencing handedness also contribute to neurodevelopmental risk.
Heritability and interpretation
Although these rare variants have measurable associations, their combined contribution to exome-wide heritability of left-handedness was estimated at approximately 0.91%. In practical terms, this means rare protein-altering variants are one piece of the puzzle but are far from the whole explanation. Common regulatory variants, environmental factors, and developmental stochasticity likely account for much of the remaining variation.
Implications and future directions
This work advances our understanding of how specific protein-altering changes can influence lateralized brain traits. Identifying TUBB4B and other microtubule-related genes implicates cellular structures that are fundamental to neuronal development, migration, and the establishment of left-right brain organization. Follow-up studies—functional experiments, developmental analyses, and more detailed phenotype correlations—will be necessary to translate these genetic signals into mechanistic insights.
The overlap between handedness-associated rare variants and genes implicated in autism and schizophrenia highlights shared developmental biology and suggests avenues for research into how early brain asymmetry relates to neurodevelopmental outcomes.
About this genetics and neurodevelopment research news
Author: Neuroscience News Communications
Source: Neuroscience News
Contact: Neuroscience News Communications – Neuroscience News
Image: The image is credited to Neuroscience News
Original Research: Open access. “Exome-wide analysis implicates rare protein-altering variants in human handedness” by Dick Schijven et al., Nature Communications.
Abstract (concise)
Handedness reflects hemispheric specialization and occurs more frequently in some neurodevelopmental disorders. While GWAS have highlighted common, mostly non-coding variants—some in tubulin and microtubule-associated genes—this study tested whether rare coding variants also influence handedness. Using exome data from 38,043 left-handed and 313,271 right-handed UK Biobank participants, the beta-tubulin gene TUBB4B reached exome-wide significance, with rare coding variants 2.7 times more frequent in left-handers. Most variants were heterozygous missense changes; two frameshifts were found exclusively in left-handed individuals. DSCAM and FOXP1, genes previously implicated in autism and schizophrenia, also showed evidence of association. The estimated exome-wide heritability for left-handedness due to rare coding variants was 0.91%, demonstrating that rare protein-altering changes contribute to handedness and implicating microtubule-related biology and disorder-relevant genes.