It is well known that left-handedness runs in families—two left-handed parents have a higher chance of having left-handed children than two right-handed parents. While this finding clearly suggests that left-handedness is to some extent heritable, the search for its underlying genetic and non-genetic causes has proven surprisingly challenging. Initially, scientists assumed that a single gene caused left-handedness, but newer studies have shown that this is not the case (Armour et al., 2014). Instead, it has been estimated that between 30 and 100 different could potentially influence handedness (McManus et al., 2013), but little progress has been made in identifying these genes.

Now, a new study has been made public on bioRxiv—a preprint server for biology—that provides important insights into the genetic determinants of left-handedness and ambidexterity (Cuellar Partida et al., 2019). By combining data from more than 30 different studies, the authors managed to gather an impressive dataset of more than 1.7 million individuals. Overall, there were 1,534,836 right-handers, 194,198 (11%) left-handers and 37,637 (2.1%) ambidextrous individuals in the dataset. Using this dataset, the authors conducted the world’s largest genome-wide association study (GWAS) of handedness.

GWAS is a technique that is commonly used in genetic research to link genetic variation with particular variations in the brain and behavior. Participants give a DNA sample (e. . a saliva, oral mucosa or blood sample) and DNA is extracted from the sample. Scientists than analyze the entire genome in these samples, by looking at hundreds of thousands or even millions of so-called SNPs (single nucleotide polymorphisms). These tiny variations in the DNA occur in everybody. By testing lots of individuals from one group (e.g. right-handers) and lots of individual from another group (e.g. left-handers) and comparing these SNPs systematically, scientists than can identify which genes differ between the two groups.

In the study by Cuellar Partida et al. (2019) the authors found 41 genetic loci associated with left-handedness and seven associated with ambidexterity that reached statistical significance. These are far more than any previous study in smaller samples has identified.

So what do these genes do?

A functional analysis revealed that the genes associated with left-handedness were involved in biological pathways important for the regulation of microtubules, the development of neurons, and hippocampus morphology. Microtubules are cellular structures that form part of the cytoskeleton—basically the structure that gives cells their shape. Microtubules are important for the proper development and migration of neurons in the brain. Thus, the functional gene groups related to left-handedness seem to be involved in brain development.

The link between microtubules and left-handedness could also shed light on one of the biggest mysteries of handedness research: the question of why patients with certain disorders, such as , have substantially elevated rates of left-handedness and ambidexterity. As mutations in genes related to microtubules have been linked to various neuropsychiatric disorders, the relevance of these structures for left-handedness may explain why patients with these disorders show changes in handedness.

Another interesting finding in the study was that the genetic correlation between left-handedness and ambidexterity was low. This suggests that there are different genetic mechanisms relevant to becoming left-handed and becoming ambidextrous. This shows that more research into ambidexterity is needed to understand this fascinating phenomenon that occurs in 1-2% of the population.

So what do the results of this study mean for left-handers? It clearly shows that left-handedness is polygenic—many different genes can play a role for whether someone is born a left-hander or not. (Differential environmental factors can also affect left-handedness.) The functional roles of the genes connected to left-handedness clearly show that it originates in the brain, not the hands itself.

Just in case you wanted to know, the full list of the genes associated with left-handedness is ST3GAL3, VANGL2, NME7, FOXN2, SH3RF3, ITGAV, MAP2, SATB1, CNTN3, ROBO2, RSRC1, FAM13A, SLC39A8, LINC02056, TMEM161B-AS1, TRIM36, BPHL, ABT1, TUBB, ECHDC1, PAX4, NDRG1, BUB3, SOX6, NPAS4, RSF1, CADM1, TUBA1B, ANKS1B, WASF3, AL133166.1, LINC00648, FURIN, ATXN2L, SNTB2, TUBB3, CRHR1, TUBB4A, RABAC1, BCR, and TTC28.

Note: As this study is still in the preprint stage and has not undergone peer-review, the contents of this blog post may be edited after the final version of the study has been published in a scientific journal.

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