Elevated levels of mixed-hand preference in dyslexia: Meta-analyses of 68 studies.

Since almost a hundred years, psychologists have investigated the link between hand preference and dyslexia. We present a meta-analysis to determine whether there is indeed an increase in atypical hand preference in dyslexia. We included studies used in two previous meta-analyses (Bishop, 1990; Eglinton & Annett, 1994) as well as studies identified through PubMed MEDLINE, PsycInfo, Google Scholar, and Web of Science up to August 2022. K = 68 studies (n = 4660 individuals with dyslexia; n = 40845 controls) were entered into three random effects meta-analyses using the odds ratio as the effect size (non-right-handers; left-handers; mixed-handers vs. total). Evidence of elevated levels of atypical hand preference in dyslexia emerged that were especially pronounced for mixed-hand preference (OR = 1.57), although this category was underdefined. Differences in (direction or degree) of hand skill or degree of hand preference could not be assessed as no pertinent studies were located. Our findings allow for robust conclusions only for a relationship of mixed-hand preference with dyslexia.

A deep phenotyping approach to assess the association of handedness, early life factors and mental health.

The development of handedness and other form of functional asymmetries is not yet understood in its critical determinants. Early life factors (e.g., birth weight, birth order) have been discussed to contribute to individual manifestations of functional asymmetries. However, large-scale data such as the UK Biobank suggest that the variance in handedness that is explained by early life factors is minimal. Additionally, atypical handedness has been linked to clinical outcomes such as neurodevelopmental and psychiatric disorders. Against the background of this triad, the current study investigated associations between different forms of functional asymmetries and (a) early life factors as well as (b) clinical outcomes. Functional asymmetries were determined by means of a deep phenotyping approach which notably extends previous work. In our final sample of N = 598 healthy participants, the different variables were tested for associations by means of linear regression models and group comparisons (i.e., ANOVAs and Chi-squared tests). Confirming previous findings from larger cohorts with shallow phenotyping, we found that birth factors do not explain a substantial amount of variance in functional asymmetries. Likewise, functional asymmetries did not seem to have comprehensive predictive power concerning clinical outcomes in our healthy participants. Future studies may further investigate postulated relations in healthy and clinical samples while acknowledging deep phenotyping of laterality.

Identification of loci involved in childhood visual acuity and associations with cognitive skills and educational attainment.

Visual acuity significantly contributes to quality of life. Deficits in childhood are associated with reading difficulties, which can have detrimental effects on education outcomes. In adults, it has been observed that vision defects such as myopia are associated with higher educational attainment (EA). Understanding genetic factors contributing to visual acuity could help to dissect its links with cognitive skills, neurodevelopmental conditions, and education. We examined associations between distance visual acuity, cognitive measures including school grades, and neurodevelopmental conditions in a longitudinal cohort of British children (ALSPAC, n = 6807, M age = 11.8). We performed a genome-wide association study (GWAS, n = 5571) on visual acuity and tested for genetic associations with relevant phenotypes using polygenic scores (PGS) and genetic correlation analyses. Visual acuity was associated with better cognitive performance and school grades, and reduced in individuals with reading difficulties compared to controls. GWAS revealed genetic associations at the NPLOC4 locus and highlighted other genes involved in sensory function. In line with positive genetic correlations between visual acuity and cognitive measures, EA PGS were positively associated with visual acuity, while there was a less robust negative association with myopia PGS. In conclusion, increased visual acuity is associated with a range of positive outcomes, including better school grades. Our results suggest an association between a higher EA PGS and slightly increased visual acuity in childhood. This could indicate gene-environment correlation, in which environmental exposures linked to higher EA might have detrimental effects on vision offsetting the initial positive effect.

Quantitative multidimensional phenotypes improve genetic analysis of laterality traits.

Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n ≤ 5028 family trios) and SNP-based heritability (SNP-h2, n ≤ 5931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h2 for quantitative handedness and footedness was 0.21 and 0.23, respectively, which is higher than the SNP-h2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (0.45) compared to a binary measure for writing hand (0.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits.

Handedness in twins: meta-analyses.

BACKGROUND: In the general population, 10.6% of people favor their left hand over the right for motor tasks. Previous research suggests higher prevalence of atypical (left-, mixed-, or non-right-) handedness in (i) twins compared to singletons, and in (ii) monozygotic compared to dizygotic twins. Moreover, (iii) studies have shown a higher rate of handedness concordance in monozygotic compared to dizygotic twins, in line with genetic factors playing a role for handedness. METHODS: By means of a systematic review, we identified 59 studies from previous literature and performed three sets of random effects meta-analyses on (i) twin-to-singleton Odds Ratios (21 studies, n = 189,422 individuals) and (ii) monozygotic-to-dizygotic twin Odds Ratios (48 studies, n = 63,295 individuals), both times for prevalence of left-, mixed-, and non-right-handedness. For monozygotic and dizygotic twin pairs we compared (iii) handedness concordance Odds Ratios (44 studies, n = 36,217 twin pairs). We also tested for potential effects of moderating variables, such as sex, age, the method used to assess handedness, and the twins' zygosity. RESULTS: We found (i) evidence for higher prevalence of left- (Odds Ratio = 1.40, 95% Confidence Interval = [1.26, 1.57]) and non-right- (Odds Ratio = 1.36, 95% Confidence Interval = [1.22, 1.52]), but not mixed-handedness (Odds Ratio = 1.08, 95% Confidence Interval = [0.52, 2.27]) among twins compared to singletons. We further showed a decrease in Odds Ratios in more recent studies (post-1975: Odds Ratio = 1.30, 95% Confidence Interval = [1.17, 1.45]) compared to earlier studies (pre-1975: Odds Ratio = 1.90, 95% Confidence Interval = [1.59-2.27]). While there was (ii) no difference between monozygotic and dizygotic twins regarding prevalence of left- (Odds Ratio = 0.98, 95% Confidence Interval = [0.89, 1.07]), mixed- (Odds Ratio = 0.96, 95% Confidence Interval = [0.46, 1.99]), or non-right-handedness (Odds Ratio = 1.01, 95% Confidence Interval = [0.91, 1.12]), we found that (iii) handedness concordance was elevated among monozygotic compared to dizygotic twin pairs (Odds Ratio = 1.11, 95% Confidence Interval = [1.06, 1.18]). By means of moderator analyses, we did not find evidence for effects of potentially confounding variables. CONCLUSION: We provide the largest and most comprehensive meta-analysis on handedness in twins. Although a raw, unadjusted analysis found a higher prevalence of left- and non-right-, but not mixed-handedness among twins compared to singletons, left-handedness was substantially more prevalent in earlier than in more recent studies. The single large, recent study which included birth weight, Apgar score and gestational age as covariates found no twin-singleton difference in handedness rate, but these covariates could not be included in the present meta-analysis. Together, the secular shift and the influence of covariates probably make it unsafe to conclude that twinning has a genuine relationship to handedness.

Genome-wide association study and polygenic risk score analysis for hearing measures in children.

An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HTs) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWASs) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by external environmental factors. Here, we investigated HT and HTA in a children population cohort (ALSPAC, n = 6,743). Better hearing was associated with better cognitive performance and higher socioeconomic status. At the group level, HTA suggested a left ear advantage (mean = -0.28 dB) that was mainly driven by females. SNP heritability for HT and HTA was 0.13 and 0.02, respectively (n = 4,989). We found a modest negative genetic correlation between HT and reading ability. GWAS for HT (n = 5,344) did not yield significant hits but polygenic risk scores for higher educational attainment (EA, ß = -1,564.72, p = .008) and schizophrenia (ß = -241.14, p = .004) were associated with lower HT, that is, better hearing. In summary, we report new data supporting associations between hearing measures and cognitive abilities at the behavioral level. Genetic analysis suggests shared biological pathways between cognitive and sensory systems and provides evidence for a positive outcome of genetic risk for schizophrenia.

Handedness and depression: A meta-analysis across 87 studies.

Alterations in functional brain lateralization, often indicated by an increased prevalence of left- and/or mixed-handedness, have been demonstrated in several psychiatric and neurodevelopmental disorders like schizophrenia or autism spectrum disorder. For depression, however, this relationship is largely unclear. While a few studies found evidence that handedness and depression are associated, both the effect size and the direction of this association remain elusive. Here, we collected data from 87 studies totaling 35,501 individuals to provide a precise estimate of differences in left-, mixed- and non-right-handedness between depressed and healthy samples and computed odds ratios (ORs) between these groups. Here, an OR > 1 signifies higher rates of atypical handedness in depressed compared to healthy samples. We found no differences in left- (OR = 1.04, 95% CI = [0.95, 1.15], p = .384), mixed- (OR = 1.64, 95% CI = [0.98, 2.74], p = .060) or non-right-handedness (OR = 1.05, 95% CI = [0.96, 1.15], p = .309) between the two groups. We could thus find no link between handedness and depression on the meta-analytical level.

MORC1 methylation and BDI are associated with microstructural features of the hippocampus and medial prefrontal cortex.

BACKGROUND: Alterations in the hippocampus and prefrontal cortex (PFC) have frequently been reported in depressed patients. These parameters might prove to be a consistent finding in depression. In addition, peripheral DNA methylation of the MORC1 gene promoter showed stable associations with depression across independent samples. However, the question arises whether MORC1, supposedly acting as transcription factor, might also be involved in neurobiological alterations accompanying depression. This study further analyses the role of MORC1 in depression by investigating a potential correlation between peripheral MORC1 DNA methylation and neuronal structural properties previously associated with depression in humans. METHODS: Beck Depression Inventory (BDI) was assessed in 52 healthy participants. DNA was extracted from buccal cells and MORC1 methylation correlated with micro- and macrostructural properties derived from magnetic resonance imaging (MRI) and neurite orientation dispersion and density imaging (NODDI) in the hippocampus and medial prefrontal cortex (mPFC). RESULTS: MORC1 methylation was associated with volume reduction and neurite orientation dispersion and density markers in the hippocampus and mPFC. BDI was positively associated with neurite orientation dispersion and density markers in the hippocampus. LIMITATIONS: The study was conducted in a small sample of healthy participants with subclinical depressive symptoms. Peripheral tissue was analyzed. CONCLUSION: We found significant negative associations between peripheral MORC1 methylation and macro- and microstructural markers in the hippocampus and mPFC. Thus, MORC1 might be involved in neurobiological properties. Studies investigating neuronal methylation patterns of MORC1 are needed to support this hypothesis.

Author Correction: A large-scale estimate on the relationship between language and motor lateralization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Four meta-analyses across 164 studies on atypical footedness prevalence and its relation to handedness.

Human lateral preferences, such as handedness and footedness, have interested researchers for decades due to their pronounced asymmetries at the population level. While there are good estimates on the prevalence of handedness in the population, there is no large-scale estimation on the prevalence of footedness. Furthermore, the relationship between footedness and handedness still remains elusive. Here, we conducted meta-analyses with four different classification systems for footedness on 145,135 individuals across 164 studies including new data from the ALSPAC cohort. The study aimed to determine a reliable point estimate of footedness, to study the association between footedness and handedness, and to investigate moderating factors influencing footedness. We showed that the prevalence of atypical footedness ranges between 12.10% using the most conservative criterion of left-footedness to 23.7% including all left- and mixed-footers as a single non-right category. As many as 60.1% of left-handers were left-footed whereas only 3.2% of right-handers were left-footed. Males were 4.1% more often non-right-footed compared to females. Individuals with psychiatric and neurodevelopmental disorders exhibited a higher prevalence of non-right-footedness. Furthermore, the presence of mixed-footedness was higher in children compared to adults and left-footedness was increased in athletes compared to the general population. Finally, we showed that footedness is only marginally influenced by cultural and social factors, which play a crucial role in the determination of handedness. Overall, this study provides new and useful reference data for laterality research. Furthermore, the data suggest that footedness is a valuable phenotype for the study of lateral motor biases, its underlying genetics and neurodevelopment.

A large-scale estimate on the relationship between language and motor lateralization.

Human language is dominantly processed in the left cerebral hemisphere in most of the population. While several studies have suggested that there are higher rates of atypical right-hemispheric language lateralization in left-/mixed-handers, an accurate estimate of this association from a large sample is still missing. In this study, we comprised data from 1,554 individuals sampled in three previous studies in which language lateralization measured via dichotic listening, handedness and footedness were assessed. Overall, we found a right ear advantage indicating typical left-hemispheric language lateralization in 82.1% of the participants. While we found significantly more left-handed individuals with atypical language lateralization on the categorical level, we only detected a very weak positive correlation between dichotic listening lateralization quotients (LQs) and handedness LQs using continuous measures. Here, only 0.4% of the variance in language lateralization were explained by handedness. We complemented these analyses with Bayesian statistics and found no evidence in favor of the hypothesis that language lateralization and handedness are related. Footedness LQs were not correlated with dichotic listening LQs, but individuals with atypical language lateralization also exhibited higher rates of atypical footedness on the categorical level. We also found differences in the extent of language lateralization between males and females with males exhibiting higher dichotic listening LQs indicating more left-hemispheric language processing. Overall, these findings indicate that the direct associations between language lateralization and motor asymmetries are much weaker than previously assumed with Bayesian correlation analyses even suggesting that they do not exist at all. Furthermore, sex differences seem to be present in language lateralization when the power of the study is adequate suggesting that endocrinological processes might influence this phenotype.

Human handedness: A meta-analysis.

Across time and place, right hand preference has been the norm, but what is the precise prevalence of left- and right-handedness? Frequency of left-handedness has shaped and underpinned different fields of research, from cognitive neuroscience to human evolution, but reliable distributional estimates are still lacking. While hundreds of empirical studies have assessed handedness, a large-scale, comprehensive review of the prevalence of handedness and the factors that moderate it, is currently missing. Here, we report 5 meta-analyses on hand preference for different manual tasks and show that left-handedness prevalence lies between 9.3% (using the most stringent criterion of left-handedness) to 18.1% (using the most lenient criterion of nonright-handedness), with the best overall estimate being 10.6% (10.4% when excluding studies assessing elite athletes' handedness). Handedness variability depends on (a) study characteristics, namely year of publication and ways to measure and classify handedness, and (b) participant characteristics, namely sex and ancestry. Our analysis identifies the role of moderators that require taking into account in future studies on handedness and hemispheric asymmetries. We argue that the same evolutionary mechanisms should apply across geographical regions to maintain the roughly 1:10 ratio, while cultural factors, such as pressure against left-hand use, moderate the magnitude of the prevalence of left-handedness. Although handedness appears as a straightforward trait, there is no universal agreement on how to assess it. Therefore, we urge researchers to fully report study and participant characteristics as well as the detailed procedure by which handedness was assessed and make raw data publicly available. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Using Mobile EEG to Investigate Alpha and Beta Asymmetries During Hand and Foot Use.

The Edinburgh Handedness Inventory (EHI) and the Waterloo Footedness Questionnaire (WFQ) are two of the most widely used questionnaires to assess lateralized everyday behavior in human participants. However, it is unclear to what extent the specific behavior assessed in these questionnaires elicit lateralized neural activity when performed in real-life situations. To illuminate this unresolved issue, we assessed EEG alpha and beta asymmetries during real-life performance of the behaviors assessed in the EHI and WFQ using a mobile EEG system. This methodology provides high ecological validity for studying neural correlates of motor behavior under more naturalistic conditions. Our results indicate that behavioral performance of items of both the EHI and WFQ differentiate between left- and right-handers and left- and right-footers on the neural level, especially in the alpha frequency band. These results were unaffected by movement parameters. Furthermore, we could demonstrate that neural activity elicited specifically during left-sided task performance provides predictive power for the EHI or WFQ score of the participants. Overall, our results show that these prominent questionnaires not only distinguish between different motor preferences on the behavioral level, but also on the neurophysiological level. Furthermore, we could show that mobile EEG systems are a powerful tool to investigate motor asymmetries in ecologically valid situations outside of the laboratory setting. Future research should focus on other lateralized behavioral phenotypes in real-life settings to provide more insights into lateralized motor functions.

Asymmetries in social touch-motor and emotional biases on lateral preferences in embracing, cradling and kissing.

In human social interaction, affective touch plays an integral role to communicate intentions and emotions. Three of the most important forms of social touch are embracing, cradling and kissing. These behaviours have been demonstrated to be lateralized, but the underlying mechanisms are still not well understood. Both motor and emotive biases have been suggested to affect laterality of social touch. We aimed to systematically investigate how motor preferences and emotive biases influence the lateralization of embracing, cradling and kissing within the same sample. Participants performed all three forms of social touch in neutral, positive and negative emotional conditions. Like a previous study, we found a rightward bias for embracing that was modulated by both motor preferences and the emotional content of the situation. Kissing and cradling were not influenced by motor preferences. In general, a negative emotional connotation of the situation led to a reduction of lateral biases in social touch, independent of the individual direction.

Schizotypy and altered hemispheric asymmetries: The role of cilia genes.

Schizophrenia patients have a higher probability of altered structural and functional differences between the left and right hemisphere. Schizotypy as its nonclinical manifestation has been related to a higher incidence of non-right-handedness and atypical right-hemispheric language dominance. It has been suggested that genes involved in cilia function might link brain asymmetry and neurodevelopmental disorders. We assessed DNA methylation in the promoter regions of seven candidate genes involved in cilia function and psychiatric disorders from buccal cells and investigated their association with schizotypy and language lateralization in 60 healthy adults. Moreover, we determined microstructural properties of the planum temporale in a subsample of 52 subjects using neurite orientation dispersion and density imaging (NODDI). We found a significant association between schizotypy and DNA methylation in the AHI1 promoter region. Moreover, AHI1 DNA methylation significantly predicted language lateralization and asymmetry in estimated planum temporale neurite density. Finally, stronger leftward asymmetry in estimated neurite density was associated with a more pronounced right ear advantage (left hemisphere dominance) in the forced-right condition of the dichotic listening task, measuring attentional modulation of language lateralization. Our results are in line with a shared molecular basis of schizotypy and functional hemispheric asymmetries that is based on cilia function.

Handedness and sex effects on lateral biases in human cradling: Three meta-analyses.

The earliest form of social contact for a newborn is being cradled by its mother. This important behavior has been found to be lateralized to the left side by many, but not all empirical studies. Factors that have been suggested to modulate cradling asymmetry are handedness and sex. However, these factors have not been demonstrated consistently, possibly due to low sample sizes and inconsistent experimental paradigms. To address this issue, we used a meta-analytical approach to (1) quantify the widely reported leftward bias in human cradling and (2) identify moderating factors of the cradling bias such as handedness and sex. Across forty studies, we observed a leftward cradling bias showing that this effect is robust and replicable. Furthermore, we found that left-handers demonstrate a significantly less pronounced leftward bias compared to right-handers and that males are less lateralized compared to females. In conclusion, we could verify that parental handedness and sex contribute to a cradling population bias. Future studies examining genetic factors could illuminate the mechanism supporting a cradling bias.

Building an Asymmetrical Brain: The Molecular Perspective.

The brain is one of the most prominent examples for structural and functional differences between the left and right half of the body. For handedness and language lateralization, the most widely investigated behavioral phenotypes, only a small fraction of phenotypic variance has been explained by molecular genetic studies. Due to environmental factors presumably also playing a role in their ontogenesis and based on first molecular evidence, it has been suggested that functional hemispheric asymmetries are partly under epigenetic control. This review article aims to elucidate the molecular factors underlying hemispheric asymmetries and their association with inner organ asymmetries. While we previously suggested that epigenetic mechanisms might partly account for the missing heritability of handedness, this article extends this idea by suggesting possible alternatives for transgenerational transmission of epigenetic states that do not require germ line epigenetic transmission. This is in line with a multifactorial model of hemispheric asymmetries, integrating genetic, environmental, and epigenetic influencing factors in their ontogenesis.

DNA methylation of dopamine-related gene promoters is associated with line bisection deviation in healthy adults.

Handedness and language lateralization are the most investigated phenotypes among functional hemispheric asymmetries, i.e. differences in function between the left and the right half of the human brain. Both phenotypes are left hemisphere-dominant, while investigations of the molecular factors underlying right hemisphere-dominant phenotypes are less prominent. In the classical line bisection task, healthy subjects typically show a leftward attentional bias due to a relative dominance of the right hemisphere for visuospatial attention. Based on findings of variations in dopamine-related genes affecting performance in the line bisection task, we first tested whether DNA methylation in non-neuronal tissue in the promoter regions of DBH, SLC6A3, and DRD2 are associated with line bisection deviation. We replicated the typical behavioral pattern and found an effect of DNA methylation in the DBH promoter region on line bisection deviation in right-aligned trials. A second exploratory analysis indicated that an overall DNA methylation profile of genes involved in dopamine function predicts line bisection performance in right-aligned trials. Genetic variation in dopamine-related genes has been linked to attention deficit hyperactivity disorder (ADHD), a neurodevelopmental trait associated with rightward attentional bias. Overall, our findings point towards epigenetic markers for functional hemispheric asymmetries in non-neuronal tissue not only for left hemisphere-dominant, but also for right hemisphere-dominant phenotypes.

The neurophysiological correlates of handedness: Insights from the lateralized readiness potential.

Handedness is the most investigated form of functional hemispheric asymmetries, but its neural correlates remain unclear. Functional imaging studies suggest differences between left- and right-handers in ipsilateral activation during unilateral hand movements, but do not allow for conclusions on the temporal dimension. In the Tapley and Bryden task, subjects have to draw as many dots as possible on a paper within 20 s using either the left or the right hand. We adapted the task for use during EEG in 36 left- and 36 right-handers. Subjects performed a visually guided response task with each trial consisting of eight motor responses. We investigated the lateralized readiness potential (LRP) at the first and last response of the sequence. Overall, increasing complexity of sequences was associated with earlier and less negative LRP peaks. For the last response, right-handers showed more negative LRP peak amplitudes than left-handers. The effect of handedness on LRP peak amplitude in the first response was modulated by task complexity with a more negative LRP peak amplitude in right-handers than left-handers in simple, but not in medium or complex trials. This effect might be due to more symmetrical processing in right-handers with increasing task complexity. These findings complement previous imaging studies and add a new perspective on the relationship between laterality and schizophrenia, associated with less pronounced LRPs and a higher prevalence of left-handedness.

Hemispheric asymmetries in cortical gray matter microstructure identified by neurite orientation dispersion and density imaging.

Histological studies have reported microstructural hemispheric asymmetries in several cortical areas of the human brain, but reliable in vivo assessment methods have been lacking so far. Here, we used neurite orientation dispersion and density imaging (NODDI) to examine microstructural asymmetries in in vivo and determine if findings are in accordance with what has been reported in histological studies. We examined intra-neurite volume fraction (INVF), neurite orientation dispersion (ODI), and isotropic volume fraction (ISO) asymmetries in two independent samples of healthy adults (n = 269 and n = 251). Over both samples, we found greater left-hemispheric INVF in early auditory, inferior parietal and temporal-parietal-occipital areas. In contrast, we found greater right-hemispheric INVF in the fusiform and inferior temporal gyrus, reflecting what has been reported in histological studies. ODI was asymmetric towards the left hemisphere in frontal areas and towards the right hemisphere in early auditory areas. ISO showed less pronounced asymmetries. There were hardly any effects of sex or handedness on microstructural asymmetry as determined by NODDI. Taken together, these findings suggest substantial microstructural asymmetries in gray matter, making NODDI a promising marker for future genetic and behavioral studies on laterality.