Non-right-handedness and psychiatric disorders: A synthesis of epidemiological, genetic, and neurobiological evidence

Abstract

Non-right-handedness (NRH), encompassing left-handedness and mixed-handedness, has been frequently reported at elevated rates in individuals with various psychiatric disorders. The consistency of this association across multiple conditions and its underlying mechanisms is the subject of ongoing investigation. This review synthesized current evidence to explore the association between NRH and psychiatric disorders from epidemiological, genetic, and neurobiological perspectives. We systematically identified and appraised relevant literature investigating NRH prevalence in psychiatric populations and potential explanatory mechanisms. Epidemiological evidence indicates an elevated prevalence of NRH, particularly within neurodevelopmental disorders. Potential contributing mechanisms identified include early developmental disruptions, shared genetic predispositions, and atypical patterns of brain lateralization. While the association between NRH and psychiatric conditions, especially neurodevelopmental disorders, is evident, the causal pathways and relative contributions of identified mechanisms are complex and debated. This review highlighted key areas requiring further research to elucidate these relationships.

Key Words: Handedness; Psychiatric disorder; Neurodevelopmental disorders; Brain lateralization/asymmetry; Interhemispheric connectivity; Early developmental disruption

Core Tip: Despite prior studies on non-right-handedness and psychiatric disorders, this review uniquely integrated epidemiological, genetic, and neurobiological evidence. It revealed higher non-right-handedness prevalence in schizophrenia, post-traumatic stress disorder, autism spectrum disorder, etc. It is linked to early developmental disruptions, genetic variants, and abnormal brain lateralization. Bidirectional causality is proposed. The review offered a novel framework and highlights future research needs.

INTRODUCTION

Handedness is defined as the preferential use of one hand over the other and is a consistent behavioral characteristic observed in the majority of humans, with 9.33% of the population identifying as left-handed, 9.49% exhibiting mixed-handedness, and the remaining 81.18% identifying as right-handed[1]. Although it may appear trivial, handedness reflects underlying cerebral lateralization and has garnered increasing interest for its potential to elucidate early neurodevelopmental processes[2]. Notably, non-right-handedness (NRH), encompassing both left-handedness and mixed-handedness, has been observed at elevated rates in various psychiatric conditions, particularly neurodevelopmental disorders, such as schizophrenia, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD)[3].

This observed association between NRH and psychiatric disorders prompts further investigation into their underlying connections. Does NRH merely reflect underlying neurodevelopmental perturbations that also predispose individuals to psychopathology? Or might NRH itself play a contributory role in shaping psychiatric risk? To address these questions, this review adopted an integrated, narrative approach that thematically organized current findings across three interconnected perspectives. First, we examined epidemiological patterns to identify which psychiatric conditions show elevated NRH prevalence and explored their shared developmental features. Second, we considered developmental and genetic mechanisms that may simultaneously influence handedness and psychiatric vulnerability, such as early life disruptions or common genetic architectures. Third, we reviewed neurobiological pathways, focusing on how alterations in brain asymmetry and interhemispheric connectivity might contribute to the observed associations between NRH and psychopathology.

To guide this synthesis, we prioritized high-quality, empirically grounded studies, including meta-analyses, genome-wide association studies (GWAS), and neuroimaging work, selected for their conceptual relevance and methodological rigor. We emphasized converging trends rather than isolated findings and reflected on areas of consistency, contradiction, and uncertainty across disciplines. Importantly, while we do not attempt to provide definitive causal answers, we proposed a working framework to contextualize NRH within the broader neurodevelopmental landscape of psychiatric disorders. By bridging epidemiology, genetics, and neurobiology, we sought to clarify the possible mechanisms behind this behavioral-neuropsychiatric link, to evaluate its clinical or developmental relevance, and to highlight promising avenues for future research and translational application.

ELEVATED PREVALENCE OF NRH IN MULTIPLE PSYCHIATRIC DISORDERS

The majority of studies have reported elevated rates of NRH, including both left-handedness and mixed-handedness, across a range of psychiatric disorders. Among psychiatric conditions, schizophrenia has been most consistently associated with increased NRH. Indeed, an earlier review by Satz and Green[4] in 1999 concluded that elevated NRH is consistently observed among patients with schizophrenia, potentially linking this to specific clinical symptoms and neuropsychological characteristics, including symptom severity and cognitive or language deficits. These conclusions were further supported by recent meta-analyses, showing approximately 1.5 to 1.8 times more likely to be NRH than the general population[3,5-7].

Beyond schizophrenia, elevated NRH has also been documented in other disorders. A recent meta-analysis of PTSD summarized an overall odds ratio (OR) of 1.8 with mixed-handedness showing an even stronger association (OR = 2.4) than left-handedness alone[8]. However, other disorders that also present with internalizing symptoms, such as depression, anxiety, and bipolar disorders, show far more mixed results. For example, a clinic-based study of 692 urban outpatient children reported higher odds of left-handedness in depression (OR = 1.5) and in anxiety (OR = 1.7)[9]. Additionally, a large population-based survey involving over 27000 adults across 12 European countries also reported that individuals who are left-handed were significantly more likely to exhibit depressive symptoms[10]. However, a second-order meta-analysis of 87 studies with over 35000 participants, despite including both of these studies, found no overall differences in NRH between depressed and healthy individuals[11].

Some studies (n > 200) reported elevated performance-related anxiety among university students with NRH[12,13]. However, higher anxiety among individuals with NRH does not imply an increased NRH proportion in anxiety disorders. Indeed, a systematic review concluded that anxiety disorders showed no consistent elevation in NRH[14]. Similarly, in bipolar disorder, large-scale studies and systematic reviews have reported no increased prevalence of NRH compared with the general population[15]. Taken together, the available evidence indicates that elevated NRH is not a general feature of affective and anxiety disorders; clear increases have so far been documented only in schizophrenia and PTSD.

By comparison, neurodevelopmental disorders constitute another subgroup that shows a markedly elevated prevalence of NRH. A meta-analysis showed that people with ASD are approximately 3.5 times more likely to have NRH, a pattern driven by 2.5 times more likely to be left-handed and 2.3 times more likely to be mixed-handed compared with controls[16]. Another study (n = 1116) found that left-handedness was similar in both the ASD and intellectual disability (ID) groups (23%-24%) while mixed-handedness was 38% in the ASD group compared with 33% in the ID group, both higher than in the healthy population[17]. Some language and reading impairment disorders, such as dyslexia and developmental language disorder (DLD), also show moderate and consistent increases in NRH (OR = 1.2) according to meta-analysis or large-scale studies[18,19].

A report has shown that individuals with dyslexia are slower overall in completing pegboard tasks; thus, the increase in NRH may be associated with their poorer two-handed coordination[20]. Similarly, individuals with developmental coordination disorder (DCD) demonstrate higher-than-average rates of left-handedness with some studies reporting prevalence rates of 14.7%-30.6%[21,22]. However, ADHD, one of the most common neurodevelopmental disorders that frequently co-occurs with DCD and shares similar motor-coordination challenges[23], shows an ambiguous relationship with NRH. For instance, a community study of 520 school-age children found no significant association between handedness and ADHD traits[24], whereas a recent meta-analysis (n > 2000) reported a borderline increase in left-handedness (P = 0.09) and a significant elevation in overall NRH (P = 0.02) compared with healthy controls[25].

Large-scale studies, particularly meta-analyses, have demonstrated that schizophrenia, PTSD, ASD, dyslexia, DLD, ID, DCD, and ADHD exhibit increased rates of NRH compared with the general population, with similar conclusions reported in a recent second-order meta-analysis examining handedness across multiple psychiatric disorders[3] (Table 1). Upon further examination, it is evident that these conditions share common characteristics, including early developmental onset and impairments in cognitive, language, or motor skills, categorizing them as neurodevelopmental or mixed-type disorders. In early childhood, ASD[26], dyslexia[27], DLD[28], DCD[29] and ADHD[30] typically present difficulties in language and motor performance. Moreover, schizophrenia, although occasionally diagnosed at a later stage, is also associated with early neurodevelopmental alterations, such as developmental delays[31,32]. PTSD, though triggered by trauma, is frequently linked to childhood adversity and developmental vulnerability factors[33,34]. Collectively, these disorders tend to reflect early deviations in brain development, especially in domains associated with higher-order cognitive or sensorimotor integration.

Table 1 Prevalence of non-right-handedness in psychiatric disorders.

Psychiatric disorder	OR or effect size	Ref.
Schizophrenia	OR = 1.5-1.8	[5-7]
PTSD	OR = 1.8 (mixed: OR = 2.4)	[8]
Depression	Inconsistent (meta-analysis: No difference)	[9-11]
Anxiety disorder	Inconsistent	[9,14]
Bipolar disorder	No increase	[15]
ASD	OR = 3.5	[16,17]
ID	Moderate increase	[17]
Dyslexia	OR = 1.2	[18]
DLD	OR = 1.2	[19]
DCD	Not always reported	[21,22]
ADHD	OR = 1.1-1.2 (borderline)	[25]

OR: Odds ratio; PTSD: Post-traumatic stress disorder; ASD: Autism spectrum disorder; ID: Intellectual disability; DLD: Developmental language disorder; DCD: Developmental coordination disorder; ADHD: Attention-deficit/hyperactivity disorder.

EARLY DEVELOPMENTAL DISRUPTION MAY CONTRIBUTE TO ELEVATED NRH IN PSYCHIATRIC DISORDERS

Given the elevated prevalence of NRH observed in psychiatric disorders discussed above, one potential explanation is that early developmental disruptions might simultaneously affect NRH and vulnerability to these disorders. Multiple studies have already indicated that early disruptions, particularly those occurring during the prenatal and perinatal periods, are associated with increased rates of NRH[35].

For several decades, scientific investigations have explored the relationship between handedness and early-life conditions. One of the earliest and most consistently documented findings is the correlation between NRH and low birth weight, with seminal studies tracing back to the 1970s[36]. Thereafter, O’Callaghan et al[37] in 1987 (n = 160) reported a 54% left-handedness rate among extremely low birth weight infants (< 1000 g) compared with just 8% in normal-birthweight controls. These findings informed the development of the “pathological left-handedness” hypothesis, which suggested that left-handedness could result from early brain insult (Satz[36] in 1972). Although this idea is now considered overly reductionist, early neural disruption remains a plausible contributor to increased NRH in vulnerable populations[1,38]. Reciprocally, large-scale studies also showed that individuals who are left-handed tend to have lower birth weight from over 2000 triplets[39] and nearly 500000 United Kingdom Biobank participants’ findings[40]. Notably, low birth weight is also recognized as a risk factor for several psychiatric disorders. It has been linked to a 1.5-2.0-fold increased risk of schizophrenia and ASD[41,42], and children born with very low birth weight (< 1250 g) also showed an increased risk of DCD[43,44].

The observed correlation between low birth weight and NRH may indeed indicate the impact of underlying prenatal or perinatal factors on the development of handedness. Research has identified several factors, such as preterm birth, intrauterine growth restriction, maternal stress, and hormonal exposure, that are associated with higher rates of NRH. Preterm birth has been associated with over a 2-fold increase in NRH risk in extremely preterm samples[45], a pattern also supported by large cohort data[1]. Intrauterine growth restriction, like polyembryony, has also been associated with elevated NRH prevalence[40]. Furthermore, severe maternal stress during pregnancy may increase NRH rates by about 30%[46,47]. Hormonal exposure, especially elevated prenatal testosterone, has been hypothesized to delay left-hemisphere development and shift functional dominance as described in the Geschwind-Galaburda hypothesis[48,49]. Reciprocally, these prenatal or perinatal influences are also well-established risk factors for various neurodevelopmental disorders, including ASD[50], ADHD[50], schizophrenia[51], and DLD[52], suggesting that these early developmental influences may underlie the elevated rates of NRH observed in these conditions.

Taken together, a growing body of research suggests that prenatal or perinatal influences, such as low birth weight, prematurity, intrauterine growth restriction, maternal stress, and atypical hormonal exposure, may jointly contribute to both elevated NRH and increased vulnerability to psychiatric disorders. These findings align with recent second-order meta-analytic evidence indicating that disorders with early developmental onset and those involving language dysfunction show particularly high rates of atypical hand preference[3]. These converging lines of evidence suggest that the impact of developmental disruptions on both handedness and psychiatric disorder vulnerability may partially account for the elevated NRH rates observed in these conditions, especially in individuals with a history of prenatal or perinatal complications.

GENETIC CORRELATIONS BETWEEN NRH AND PSYCHIATRIC DISORDERS

Beyond early developmental disruptions, another prominent explanation for the NRH-psychiatric disorder association is that they share common genetic underpinnings. Although handedness is a stable and commonly considered heritable trait, its heritability estimated from genetic studies is relatively modest. Twin studies estimate that the heritability of handedness is approximately 25%[53] while single-nucleotide polymorphism-based heritability from large-scale GWAS is lower, typically around 3%-6%, and narrow-sense heritability is 11.9%[54,55]. This suggests that while handedness is genetically influenced, it is not strongly determined by genetic variation alone. In contrast, many psychiatric disorders, such as schizophrenia, ASD, and ADHD, show considerably higher heritability, often exceeding 70%[56-58]. Given the relatively low heritability of handedness compared with most psychiatric disorders, the genetic overlap between NRH and these conditions is likely constrained, and its contribution to their phenotypic association remains unclear.

Early candidate gene-based genetic studies have reported that some specific loci might be associated with both left-handedness and mixed-handedness as well as an elevated risk of psychiatric disorders. For example, variants in leucine rich repeat transmembrane neuronal 1, an imprinted gene on chromosome 2p12, were initially reported to be associated with both left-handedness in families with dyslexia and schizophrenia susceptibility[59,60]. Similarly, variants of proprotein convertase subtilisin/kexin type 6 were implicated in influencing handedness strength, particularly among individuals with dyslexia and ASD[61,62].

However, these associations have largely failed to replicate in subsequent GWAS, questioning the validity of early candidate gene findings[55]. A recent large-scale meta-analytic GWAS study involving over 1.7 million individuals identified 41 loci associated with left-handedness and 7 with mixed-handedness[55]. Importantly, several handedness-associated loci also showed genetic correlations with schizophrenia and bipolar disorder, with specific variants (e.g., rs6224, rs13107325, and rs45527431) demonstrating concordant effects on both traits[55]. Beyond specific loci, tissue, and pathway enrichment analyses consistently highlight central nervous system structures and developmental pathways that may contribute to psychiatric disorder vulnerability, such as microtubule regulation, axonogenesis, and cerebral cortex morphology[55,63].

In particular, multiple handedness-associated genes, including tubulin beta class I (TUBB), TUBB3, TUBB4A, microtubule-associated protein 2, and N-myc downstream regulates gene-1, encode proteins involved in microtubule dynamics and neuronal development, which are essential processes during early brain organization and hemispheric specialization[63]. These same genes have also been implicated in psychiatric disorders, such as schizophrenia[64] and ASD[65]. This convergence suggests that microtubule-related genetic pathways may influence both cerebral asymmetry and neural circuit formation, thereby linking handedness with psychopathology at the neurodevelopmental level. However, it is crucial to note that these limited genetic associations have small effect sizes with individual variants typically explaining < 0.1% of the liability variance in handedness. Given such limited genetic determination, the shared genetic component likely accounts for only a small portion of the NRH-psychiatric disorders association. Moreover, recent exome-wide analyses have shown that rare protein-altering variants also contributed minimally to handedness heritability[54]. Therefore, although shared genetic underpinnings represent the most intuitive hypothesis, their actual explanatory power remains highly questionable.

BRAIN LATERALIZATION IN NRH AND PSYCHIATRIC DISORDERS

From a neurobiological perspective, another potential explanation for the handedness-psychiatric disorder association lies in brain asymmetry patterns. Different handedness preferences reflect underlying cerebral lateralization differences that may be related to psychiatric disorders that have been widely documented to exhibit various forms of brain asymmetry abnormalities.

Most individuals who are right-handed exhibit dominant left-hemisphere control for fine motor tasks, supported by characteristic structural and functional brain asymmetries[66]. Neuroimaging studies have confirmed that left-handers are more likely to exhibit atypical (e.g., bilateral or rightward) hemispheric dominance compared with right-handers[67,68]. Beyond motor lateralization, handedness is also closely linked to language lateralization[67-69]. While the majority of individuals exhibited left-hemisphere dominance for language-related brain regions, individuals with NRH are more likely to demonstrate atypical language lateralization, often characterized by rightward shifts that mirror their atypical motor-related lateralization[67-69]. This evidence suggests that individuals with NRH may exhibit reduced structural and functional brain asymmetry in relevant regions, leading to less pronounced hemispheric dominance for specific cognitive and motor functions compared with those who are right-handed.

Reciprocally, reduced brain asymmetry has also been documented across multiple psychiatric disorders. The ENIGMA consortium has systematically examined brain asymmetry patterns in several handedness-related psychiatric conditions through large-scale meta-analyses. For instance, in ADHD pediatric patients demonstrated reduced rightward asymmetry of total hemispheric surface area[70]. Similarly, patients with ASD often exhibited diminished asymmetry in cortical thickness across multiple brain regions[71]. In schizophrenia, while overall cortical thickness and surface area asymmetries did not significantly differ between cases and controls, patients showed significantly reduced asymmetries in thickness within specific regions, including the middle temporal gyrus and rostral anterior cingulate cortex[72]. Further extending this pattern, other neurodevelopmental conditions like DCD[73], dyslexia[74], and DLD[74] also exhibit atypical brain lateralization. These findings predominantly involve reduced hemisphere dominance in functional activation or connectivity within sensorimotor (DCD) and language (dyslexia, DLD) networks. Structural alterations, such as reduced leftward asymmetry of the planum temporale, have also been reported in boys with dyslexia[74].

Despite these convergent findings, the relationship between reduced brain asymmetry, handedness, and psychiatric disorders appears more complex than once thought. One challenge lies in the fact that studies simultaneously investigating the influence of both NRH and psychiatric disorders on brain asymmetry are still quite limited. For instance, one study investigating brain asymmetry with both schizophrenia and NRH (n = 100 per group) identified an NRH-associated rightward shift in grey matter volume of the superior temporal gyrus but failed to detect a significant interaction between schizophrenia and NRH[75]. However, it cannot be ruled out that the limited sample size lacked sufficient statistical power to detect such interactions, especially given the subtle nature of cerebral asymmetric alterations and the higher power required for interaction analyses.

Another point of consideration is that large-scale brain asymmetry studies of psychiatric disorders (such as those from the ENIGMA consortium) have generally not observed a significant influence of handedness on disease-related brain asymmetry changes (a finding potentially limited by the low prevalence of left-handedness). These studies at least partially suggest that the similar patterns of reduced brain asymmetry observed in both disorders and NRH are not merely a consequence of the elevated NRH proportion within psychiatric populations.

In addition to lateralization patterns, interhemispheric connectivity, particularly via the corpus callosum (CC), has been implicated in the neurobiology of handedness[76-78]. The CC is the largest white matter tract in the brain and plays a critical role in facilitating interhemispheric communication[79]. Earlier studies reported that individuals with NRH exhibit larger CC volumes compared to right-handers[80]. However, a recent meta-analysis found no significant differences in overall CC size across different handedness groups[81]. This result may be partly explained by another study that suggested a negative correlation between CC thickness and the degree of handedness lateralization rather than its direction[82], implying that studies based on a dichotomous classification of handedness might not readily observe such subtle variations.

Furthermore, beyond gross callosal anatomy, some studies suggest that microstructural differences within the CC may also vary with handedness[76,83], although these investigations typically involve small sample sizes. Moreover, tissue enrichment analyses of handedness-associated genetic loci have also highlighted the CC as a highly relevant brain region[55]. While human studies on overall CC size yield mixed results, animal models also provide evidence that agenesis or disruption of the CC in rodents leads to a reduction in paw preference, underscoring that callosal dysfunction impairs the establishment of lateralized motor behavior[84,85]. However, it is crucial to distinguish this from human mixed-handedness; in rodents, it refers to inconsistent use of a single paw in a specific task, whereas in humans, mixed-handedness is defined by the preferential use of different hands for different tasks.

Regarding psychiatric disorders, multiple conditions are frequently associated with CC abnormalities. However, contrary to the prevailing notion that NRH is associated with larger CC, reduced CC is frequently observed in psychiatric disorders, including schizophrenia[86-88], ASD[89,90], and ADHD[91,92]. Nevertheless, opposite effects have also been reported. For example, a study of patients with neuroleptic-naïve recent-onset schizophrenia revealed a significant increase in the area of the anterior CC[93]. Similarly, an ASD study also found increased anterior CC area and thickness in infants with ASD (age = 2 years), correlating with repetitive behavior[94]. These findings suggest that the direction of CC changes in disorders may be associated with disease duration, with early-stage alterations possibly mirroring observations in NRH populations.

Abnormalities of the CC have been proposed to reflect changes in interhemispheric connectivity that may be associated with both handedness and psychiatric disorders. In line with this, a study reported that individuals who are right-handed have stronger interhemispheric functional connectivity between the left primary motor cortex and the contralateral right premotor cortex compared with those who are left-handed[95]. Furthermore, as suggested by Innocenti et al[96], these CC changes may also reflect reduced thalamic input. Notably, a recent multivariate GWAS revealed significant heritability in right thalamic connections and identified a positive correlation with the polygenic score for left-handedness (r = 0.07, P = 1.74 × 10^-31)[78]. In summary, cerebral lateralization and interhemispheric communications, particularly via the CC, may play crucial roles in the association between handedness and psychiatric disorders.

DISCUSSION

Current evidence suggests a consistent association between elevated rates of NRH and several psychiatric disorders, while the underlying mechanism for these associations is still largely unclarified. The early development interruption, shared genetic underpinnings, and atypical brain asymmetry may partially explain such associations. However, existing evidence from these potential mechanisms remains insufficient to fully elucidate the interactive effects between NRH and psychiatric disorders. Specifically, it remains unclear whether NRH and psychiatric disorders represent unrelated parallel consequences of shared factors (e.g., prenatal disruptions), whether they stem from common underlying mechanisms (e.g., shared genetic vulnerabilities) or whether a direct causal relationship exists between them.

One prevalent hypothesis posits that NRH as a stable and heritable trait serves as a risk factor for psychiatric disorders[75]. This is often attributed to NRH-associated brain lateralization changes, such as weak asymmetry, which are hypothesized to increase the risk of these disorders[68]. Furthermore, genetic variations influencing brain lateralization are often considered co-risk factors for both conditions[63]. However, such hypotheses currently lack sufficient multilevel empirical support. First, it remains uncertain whether observed brain lateralization changes related to NRH are a cause or a consequence of NRH. Second, the debate continues regarding whether altered brain lateralization genuinely increases the risk of psychiatric disorders. For instance, Bishop[97] proposed that weak asymmetry might be a consequence of dyslexia/specific language impairment-related learning impairment rather than its cause. Lastly, even the potential causal direction between NRH and psychiatric disorders remains ambiguous.

Given that handedness is widely considered to reflect innate and stable neurobiological organization, researchers have often hypothesized that NRH might influence psychiatric disorders based on the typical onset sequence. Some researchers, such as Hepper et al[98], have demonstrated that hand preference may emerge as early as the fetal stage as evidenced by in utero thumb-sucking asymmetry, suggesting that aspects of handedness may be biologically programmed before birth[98]. Conversely, many NRH-associated disorders exhibit a later onset pattern, predominantly emerging during childhood or adolescence, such as ASD, schizophrenia, and PTSD[99]. Therefore, it is unlikely that the latter disorders can influence a fetal-determined trait. However, other studies suggest that the significant lateralization of handedness may not be fully established until approximately 2 years of age[100,101], evolving through a protracted developmental trajectory.

Furthermore, an adoption study found no significant differences in handedness between individuals influenced by biological parents vs adopted parents when adoption occurred in the infant period[102]. These findings collectively underscore the profound influence of postnatal development on NRH. Crucially, this developmental window for handedness can overlap with the early manifestation of several psychiatric conditions, such as ASD[103] and schizophrenia[104]. In addition, general early psychiatric risk factors, such as cognitive deficits or early life stress, may also influence handedness development[105]. Therefore, there may exist the possibility of reverse or bidirectional causality. Rather than NRH serving solely as a risk factor for psychiatric disorders, early disruptions in brain development related to emerging psychopathology may also shape the trajectory of handedness.

While these discussions shed light on the multifaceted nature of the NRH-psychiatric disorder association, a clearer understanding is still hindered by critical limitations in the field. Specifically, the neuropsychological mechanisms underlying both handedness and psychiatric disorders, particularly regarding handedness itself, remain incompletely understood. Despite decades of research, the developmental, genetic, and neurobiological determinants of handedness remain poorly characterized.

CONCLUSION

NRH is overrepresented in several psychiatric disorders, especially those with early onset and cognitive or motor impairments. Although early developmental disruption, overlapping genetic architecture, and atypical brain lateralization are proposed contributors to this pattern, their relative contributions and interactions remain unclear (Figure 1). NRH may precede, accompany, or result from emerging psychopathology. For instance, although handedness emerges prenatally and consolidates in early childhood, neurodevelopmental disruptions or early symptoms of psychiatric disorders could interfere with its typical establishment. Conversely, NRH could act as a proxy marker for subtle brain anomalies that predispose to mental illness.

Figure 1 Proposed mechanistic pathways linking psychiatric disorders and non-right-handedness. LRRTM1: Leucine rich repeat transmembrane neuronal 1; PCSK6: Proprotein convertase subtilisin/kexin type 6; TUBB: Tubulin beta class I; MAP2: Microtubule-associated protein 2.

Beyond theoretical implications, these findings hold potential applied relevance. NRH, as a non-invasive and easily observable trait, may serve as a developmental risk marker for neuropsychiatric conditions when considered alongside other early indicators such as language or motor delays. Although it lacks diagnostic specificity, routine assessment of handedness in pediatric or clinical settings may help inform early screening frameworks or individualized neurodevelopmental monitoring protocols. Moreover, atypical handedness may provide a behavioral window into cerebral lateralization profiles, which could inform neuropsychological evaluation strategies.

To advance both scientific understanding and translational utility, future research should prioritize longitudinal and mechanistic approaches. Large-scale, prospective cohort studies beginning in infancy and incorporating handedness trajectories, neuroimaging, cognitive profiling, and genetic data will be crucial for clarifying the temporal dynamics and causal relationships between NRH and psychiatric outcomes. Parallel development of animal models capable of manipulating lateralized behavior will also enable direct testing of mechanistic hypotheses. Ultimately, these efforts will help determine whether NRH can be leveraged as an early, low-cost signal to guide risk stratification and early intervention in vulnerable populations.