The molecular genetics of hand preference revisited

Abstract

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

Genome sequencing for rightward hemispheric language dominance

“…63,64 A relatively small-scale genome-wide association study in humans reported that genes involved in visceral laterality showed an enrichment of association signals with left-vs-right hand motor skill, 65 but a much larger study of binary-trait handedness in the UK Biobank data set, based on roughly 350 000 subjects, found no genetic link of handedness to visceral asymmetry genes. 30 Early life factors can also influence handedness, including birth weight, twinning and breastfeeding, but to an extent which is not remotely predictive at the individual level. 54 Intriguingly, it may be that situs inversus of the visceral organs does associate with left-handedness when not due to mutations affecting the nodal ciliary pathway, 23 although no causal genes were identified in a recent study which investigated the trait combination of situs inversus and left-handedness without PCD.…”

“…58 genes related to PCD and asymmetry disorders 18 ; 62 genes either implicated in visceral asymmetry disorders or known to be involved in the visceral left-right developmental pathway, 20 as well as a final set of 18 candidate genes which have been tentatively associated with human brain laterality in previous studies. 14,30,32 The GO terms were defined within AmiGO's 52,53 direct annotation (http://geneontology.org/gene-associations/goa_human.gaf.gz, downloaded 16-Nov-2017). Additional sets were investigated post hoc as child sets of the actin cytoskeleton set (Table S2).…”

“…Recent analyses using the UK biobank data set, based on more than 300 000 participants, have reported that alleles of the microtubule-associated gene MAP2 have very small effects on the probability of becoming left-handed, as well as some other loci which did not clearly implicate individual genes. 30,31 However, the rarer trait of RHLD, found in only roughly 10% of left-handers and less than 1% of right-handers, has not been subject to any previous molecular genetic studies. By analogy with SIT, here we investigated whether RHLD might sometimes arise due to high-penetrance genetic mutations.…”

“…The candidate sets included genes involved in visceral laterality or the actin cytoskeleton, as well as a set of 18 genes which have been tentatively associated with human brain laterality in previous studies. 14,30,32 2 | METHODS…”

Different laterality indexes are poorly correlated with one another but consistently show the tendency of males and females to be more left- and right- lateralised, respectively

“…A difficulty in demonstrating this assumption is the availability of adequate datasets. While hand preference data are easy to collect in extremely large samples through self-reported questionnaire (17), performance tests are expensive and time-consuming. Therefore, collecting performance data in large samples is challenging, making it difficult to compare and evaluate correlations across tests.…”