From single-gene theories to polygenic biology: how the science changed completely

Introduction

The genetics of handedness has undergone one of the most dramatic transformations in behavioural science. For much of the twentieth century, researchers sought a single genetic explanation for left-handedness. Modern genomic research has overturned that view entirely.

Large-scale genome-wide association studies now demonstrate that handedness is a complex, polygenic trait influenced by many genetic variants, prenatal developmental processes, and stochastic biological factors. No single gene controls whether you write with your left hand. Instead, hundreds of genetic variants each contribute a tiny push, and even taken together they leave much of the variation unexplained.

How Much Is Inherited?

The first indication that handedness has a biological basis came from family and twin studies. Left-handedness clearly runs in families:

Exact figures vary between studies and populations, but the overall picture is remarkably consistent – left-handedness runs in families, but genetics is only part of the story. Most children of two left-handed parents are still right-handed.

Twin studies

The most influential twin study of handedness remains:

Medland SE et al. (2009). "Genetic influences on handedness: Data from 25,732 Australian and Dutch twin families." Neuropsychologia.

This study estimated heritability at approximately 20–25%, meaning genetics explains roughly a fifth to a quarter of individual variation in handedness. The remainder reflects a combination of prenatal development, developmental randomness and environmental influences. This estimate remains broadly consistent with modern genomic data, although SNP-based heritability estimates from GWAS tend to be lower – around 8–10% from common variants alone. The reasons for that gap remain unresolved and may include rare variants, gene-gene interactions and other genetic or developmental effects not captured by standard GWAS.

The Failure of Candidate Gene Approaches

Through the 1990s and early 2000s, researchers tested individual genes they believed might influence handedness. Several attracted particular attention:

• LRRTM1 — reported by Francks et al. (2007) as associated with both left-handedness and schizophrenia; generated considerable excitement but proved difficult to replicate
• PCSK6 — implicated in left-right body asymmetry in other organisms; some association signals in small human studies
• COMT — a gene involved in dopamine metabolism; proposed links to handedness were not consistently supported
• SETDB2 — suggested in some analyses but similarly failed to replicate robustly

The pattern repeated itself across the field: initial findings, then failed replications. This was not simply bad science — it was the predictable consequence of searching for large-effect genes in a trait that does not have them. Studies that were underpowered to detect small effects would occasionally find spurious signals by chance. The candidate-gene era is now regarded as a cautionary example across behavioural genetics, not just handedness research.

The GWAS (Genome Wide Association Study) Revolution

Everything changed when researchers gained access to genome-wide association study (GWAS) technology and, crucially, the sample sizes large enough to use it meaningfully.

Rather than testing a handful of candidate genes, GWAS examines millions of genetic variants across the entire genome simultaneously. Detecting small effects requires enormous samples — and that is exactly what large-scale biobank studies eventually delivered.

The landmark study:

Cuellar-Partida G et al. (2021). "Genome-wide association study identifies 48 common genetic variants associated with handedness." Nature Human Behaviour.

Sample size: approximately 1.7 million individuals.

Results: 48 genome-wide significant genetic loci associated with handedness, plus many additional suggestive signals.

Key conclusion: no single variant explained a meaningful proportion of handedness. The effects were tiny and distributed across many regions of the genome. This definitively ended serious scientific support for single-gene models of handedness.

What Do the Genes Actually Do?

Identifying associated variants is only the first step. The more important question is what those genes do biologically.

The answer is complex. Genes associated with handedness are involved in several aspects of early development, including:

• Neuronal migration — how neurons travel to their correct positions during brain development
• Axon guidance — how nerve fibres find their correct targets
• Neural connectivity — how brain regions form connections with one another
• Cytoskeletal organisation — the internal scaffolding of cells, particularly relevant to early developmental asymmetry

Of these, one particularly interesting theme has appeared repeatedly: the cytoskeleton – the internal scaffolding of cells – and especially microtubules.

Taken together, these findings suggest that handedness does not arise from a gene that says "use the left hand." Instead, it appears to emerge from biological processes involved in establishing asymmetry across the developing nervous system much earlier in development.

The Microtubule Hypothesis

One of the most intriguing convergent findings concerns microtubule biology.

Microtubules are protein structures that form the internal scaffolding of cells. They are involved in intracellular transport, cell shape maintenance, and the movement of chromosomes during cell division. In neurons, they play a critical role in axon growth and the establishment of directionality within nerve cells.

Several handedness-associated genes participate in microtubule-related pathways. Sha et al. (2021) specifically found that genetic influences associated with handedness were enriched for microtubule-related biological processes.

The significance is this: if microtubule biology does influence handedness, it raises the intriguing possibility that some of the foundations of hand preference are established at the cellular level during very early embryonic development – before obvious hand preference or purposeful reaching emerges. The asymmetry may therefore have its origins, at least in part, in how cells organise themselves, rather than simply in how the brain later directs movement

Schijven D et al. (2024). Exome-wide analysis implicates rare protein-altering variants in human handedness. Nature Communications.

This study drew on UK Biobank exome data — exome sequencing reads only the protein-coding portion of the genome (roughly 1–2% of the total), the part that most directly determines how proteins are built and function, rather than scanning the whole genome as GWAS does. From 38,043 left-handers and 313,271 right-handers, this study identified rare protein-altering variants in TUBB4B — a gene encoding a beta-tubulin protein involved in microtubule structure — at 2.7 times the rate in left-handers compared with right-handers (0.076% versus 0.028%). The variants were mostly heterozygous missense changes (swapping one amino acid for another usually has a mild effect), but did include two frameshift variants (mutations that shift the gene's reading frame downstream, typically producing a severely disrupted protein) found only in left-handers. The absolute numbers matter for interpretation: roughly one left-hander in 1,300 carries such a variant, and rare coding variants across the exome accounted for only 0.91% of the heritability of left-handedness. Their significance therefore lies not in explanatory power but in direction — they point to a specific developmental mechanism. The same analysis also found rare coding variants in DSCAM and FOXP1 associated with left-handedness. Both genes have separately been linked to autism and schizophrenia in other exome studies — not because handedness is connected to either condition, but because genes like these often play several unrelated roles in early brain development. Article 4 explores this shared-developmental-origins idea in more detail.

Prenatal Origins

Genetic findings increasingly align with independent developmental evidence that handedness emerges before birth.

• Foetal ultrasound studies have documented movement asymmetries — preferential arm movements — from as early as the first trimester
• Thumb-sucking studies have shown that foetuses preferentially suck the thumb of the hand that will become their dominant one
• Genetic factors associated with handedness are active during early neural development, not only in later life

Ocklenburg S et al. (2017). Ontogenesis of lateralization. Neuroscience and Biobehavioral Reviews.

This comprehensive review confirmed that multiple independent lines of evidence point to prenatal origins for handedness, and that the process likely involves a cascade of developmental steps rather than a single determining event.

The Missing Heritability Problem

Despite major advances, an important puzzle remains. Twin studies suggest that genetics explains around 20–25% of handedness variation. Known common genetic variants from GWAS account for only a fraction of that — roughly 8–10%. The gap — sometimes called "missing heritability" — is real and unresolved.

Possible explanations include:

• Rare variants with larger individual effects (such as TUBB4B variants) not captured by standard GWAS
• Gene-gene interactions that are not detectable in single-variant analyses
• Epigenetic influences — modifications to gene expression that are not encoded in DNA sequence
• Developmental stochasticity — random variation in how genes are expressed during development

Developmental Randomness

One of the most counterintuitive — and important — insights of modern handedness research is that genetics does not fully determine handedness even in principle.

Even genetically identical individuals can develop different handedness. A large meta-analysis found identical twins were concordant for handedness about 80% of the time – meaning roughly one in five pairs differed despite sharing virtually the same DNA. This is one reason researchers consider developmental stochasticity – random variation in biological processes during development – an important part of the explanation.

McManus C (2019). Half a century of handedness research: Myths, truths; fictions, facts; backwards, but mostly forwards. Brain and Neuroscience Advances, 3.

This review argues that random developmental processes likely play a substantial and irreducible role in determining individual handedness outcomes — a view now broadly accepted in the field.

Current Scientific Consensus

Strongly supported:

• Handedness is partly heritable, with heritability estimated at 20–25%
• No single handedness gene exists
• Handedness is highly polygenic — many variants, each with a tiny effect
• Prenatal development is critical to establishing hand preference
• Genes involved in neural development and cytoskeletal organisation are repeatedly implicated
• Microtubule pathways appear specifically relevant
• Developmental randomness is a genuine and substantial contributor

Moderately supported:

• Epigenetic influences may contribute
• Rare variants (such as TUBB4B) provide mechanistic clues even if they explain little variance
• Some genetic overlap exists between handedness and neurodevelopmental traits

Unresolved:

• Why handedness stabilises at approximately 10% left-handedness across very different populations and cultures
• The precise embryological sequence by which genetic asymmetry becomes behavioural handedness
• The exact contribution of developmental randomness to individual outcomes

Written by Anything Left-Handed

Specialists in left-handed products and information since 1968. We have been collecting left-handers' own accounts for longer than most of this research has existed.

We are not geneticists. This is a review of published research, not original work. We say where the evidence is thin, we name the studies we relied on, and we correct ourselves when we get something wrong.

Last reviewed October 2026.

References

• Cuellar-Partida G et al. (2021). Genome-wide association study identifies 48 common genetic variants associated with handedness. Nature Human Behaviour.
• Sha Z et al. (2021). Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals. PNAS.
• Schijven D et al. (2024). Exome-wide analysis implicates rare protein-altering variants in human handedness. Nature Communications.
• Francks C (2019). Exploring human brain lateralization with molecular genetics and genomics. Annals of the New York Academy of Sciences.
• Medland SE et al. (2009). Genetic influences on handedness: Data from 25,732 Australian and Dutch twin families. Neuropsychologia.
• Ocklenburg S et al. (2017). Ontogenesis of lateralization. Neuroscience and Biobehavioral Reviews.
• McManus C (2019). Half a century of handedness research: Myths, truths; fictions, facts; backwards, but mostly forwards. Brain and Neuroscience Advances, 3.

Read the accessible introduction to this topic: Is There a Left-Handed Gene?