Genome Regions Associated With Left-handedness Identified For the First Time

Handedness, whether an individual is dominantly right or left-handed, is a concept that has puzzled scientists for many years. 90% of the population are right-handed. Why is it that right-handedness is dominant? What factors determine whether an individual is right or left-handed?

The history of "lefties" in humanity

Historical clues suggest that "lefties" (a left-handed individual) have existed in the human population for millions of years. Archaeological and paleontological explorations have uncovered ancient weapons and tools that were designed for left-handed use. Palaeolithic humans left their mark on the world – quite literally – by adorning cave walls with hand-print paintings. Expert analysis of such paintings has revealed that the artists were both right and left-handed individuals.¹ 

In the past, society subjected lefties to quite extreme stigmatization. In the seventeenth century, religious groups believed that the Devil baptized his followers with his-left hand, and thus being left-handed was regarded as a "sinister" trait – an association with evil. 

Later, science reduced left-handedness to a pathology. Cesare Lombroso declared left-handedness a biological abnormality. He believed that favouring the right brain hemisphere over the left meant that an individual was more criminally inclined: "In criminals and lunatics the right lobe predominates very much more often than in normal persons…while the healthy man thinks and feels with the left lobe, the abnormal, thinks, wills, and feels more with the right.”²

Thankfully, society no longer adopts such a primitive view towards left-handedness; it is an accepted trait that's negative connotations have been shed over time. Nonetheless, the biological mechanisms determining handedness remain a subject of debate for scientists. 

Can genetics unlock the secret to handedness? 

Twin studies have demonstrated that ~25% of the variation in handedness can be explained by genes, but the specific genes involved have not been conclusively identified. That is – until now.

A new scientific study has – for the first time – identified regions of the genome that are associated with being left-handed and linked the effect of these genes with the brain's architecture, specifically regions associated with language.

The study was conducted by researchers at the University of Oxford and is published in the journal Brain.³

The experimental design of the study included analyzing the genomes of approximately 400,000 people from the UK Biobank. The sample included 38,332 left-handers. Coupling this information with brain imaging data, the researchers aimed to discover correlations between:

• handedness phenotype and image derived phenotypes (IDPs)
  
  
• genotype and handedness
  
  
• handedness-related genotypes and IDPs

The imaging data from the UK Biobank were processed to design and create a set of IDPs to be used in the study. These were normalized to ensure normality and confounds including age, sex and head size.

Akira Wiberg, a Medical Research Council fellow at the University of Oxford, who carried out the analyses, said: "Many researchers have studied the biological basis of handedness, but using large datasets from UK Biobank has allowed us to shed considerably more light on the processes leading to left-handedness."

Handedness develops in the womb?

The genomic analyses revealed four significant loci associated with left-handedness. The top SNP associated with handedness was rs199512. This SNP is located in a gene that encodes proteins involved in brain development and axonal guidance (WNT3, MAPT, MAPT-AS1).

Combining the genetic analyses with brain imaging data, the researchers show that this SNP yielded highly significant associations with measures of white matter structural connectivity. These differences were revealed more strongly in the tracts that link Broca's and tempoparietal junction areas involved in language.

"We discovered that, in left-handed participants, the language areas of the left and right sides of the brain communicate with each other in a more coordinated way. This raises the intriguing possibility for future research that left-handers might have an advantage when it comes to performing verbal tasks, but it must be remembered that these differences were only seen as averages over very large numbers of people and not all left-handers will be similar."

Professor Gwenaëlle Douaud, joint senior author on the study, from the Wellcome Centre for Integrative Neuroimaging at the University of Oxford, said: ""For the first time in humans, we have been able to establish that these handedness-associated cytoskeletal differences are actually visible in the brain. We know from other animals, such as snails and frogs, that these effects are caused by very early genetically-guided events, so this raises the tantalising possibility that the hallmarks of the future development of handedness start appearing in the brain in the womb."

The literature has suggested a link between left-handedness in a variety of psychiatric disorders based on meta-analyses data. In line with this, the researchers discovered a statistically significant positive correlation between left-handedness and schizophrenia. However, they are quick to stress that these links only correspond with a small difference in the actual number of individuals with this condition and are correlational – they therefore do not show cause and effect. They do suggest, however, that studying the genetic links identified here could improve our understanding of how such medical conditions progress.  

The rich tapestry that makes us human

Professor Dominic Furniss, joint senior author on the study, from the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science at the University of Oxford, said: "Throughout history, left-handedness has been considered unlucky, or even malicious." He continues: "Here we have demonstrated that left-handedness is a consequence of the developmental biology of the brain, in part driven by the complex interplay of many genes. It is part of the rich tapestry of what makes us human."

References:

1.       Gutwinski et al. 2011. Understanding Left-Handedness. Dtsch Arztebl Int. doi: 10.3238/arztebl.2011.0849.

2.       Kushner. 2011. Cesare Lombroso and the pathology of left-handedness. The Lancet. DOI: https://doi.org/10.1016/S0140-6736(11)60009-3.

3. Wiberg et al. 2019. Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics. Brain. https://doi.org/10.1093/brain/awz257