Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals

Abstract

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7-mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

Keywords: brain asymmetry; cerebral cortex; gene–brain–behavior; left-handedness; polygenic scores.

Fig. 1.

Handedness-associated cortical surface area asymmetries. (A) Group average differences of cortical surface area asymmetry between 28,802 right-handers and 3,062 left-handers shown for the whole cortex, without a threshold for significance. Red color indicates a lower asymmetry index in left-handers (weaker average leftward or stronger average rightward asymmetry in left-handers compared to right-handers). Blue indicates a higher asymmetry index in left-handers (stronger average leftward or weaker average rightward asymmetry in left-handers compared to right-handers). (B) Regional clusters with significant group average differences of surface area asymmetry between 28,802 right-handers and 3,062 left-handers. There were eight clusters that survived multiple testing correction (vertex-wise P < 0.001; cluster-wise P < 0.05). For all clusters, the effects were positive (weaker average leftward or stronger average rightward asymmetry in left-handers compared to right-handers). The clusters are shown on an inflated cortical surface model to visualize effects within folded regions. See also SI Appendix, Fig. S3, which shows the same maps against Brodmann regional atlas boundaries, for reference.

Fig. 2.

Handedness-associated cortical thickness asymmetries. (A) Group average differences of cortical thickness asymmetry between 28,802 right-handers and 3,062 left-handers shown for the whole cortex, without a threshold for significance. Red color indicates a lower asymmetry index in left-handers (weaker average leftward or stronger average rightward asymmetry in left-handers compared to right-handers). Blue indicates a higher asymmetry index in left-handers (stronger average leftward or weaker average rightward asymmetry in left-handers compared to right-handers). (B) Regional clusters with significant group average differences of cortical thickness asymmetry between 28,802 right-handers and 3,062 left-handers. There were two clusters that survived multiple testing correction (vertex-wise P < 0.001; cluster-wise P < 0.05). For both clusters, the effects were positive (weaker average leftward or stronger average rightward asymmetry in left-handers compared to right-handers). The clusters are shown on an inflated cortical surface model to visualize effects within folded regions. See also SI Appendix, Fig. S4, which shows the same maps against Brodmann regional atlas boundaries, for reference.

Fig. 3.

Functional annotation of regions that show altered asymmetry in left-handedness. Functional annotation based on meta-analyzed fMRI data for clusters showing altered surface area asymmetry (A) and cortical thickness asymmetry (B) in left-handedness. (Left) Coactivation maps for the handedness-associated clusters derived from the “decoder” function of Neurosynth (higher z-scores indicate greater coactivation). (Right) Cognitive terms associated with the coactivation maps for handedness-associated clusters. Only terms with correlations >0.2 between their meta-analytic activation maps and the coactivation maps for handedness-associated clusters are shown. See also SI Appendix, Table S3.

Fig. 4.

Genetic influences on hand preference impact some of the cortical asymmetries linked to hand preference. Five clusters of handedness-associated cortical surface area asymmetry showed significant heritabilities after FDR correction (i.e., three clusters in the anterior insular cortex [clusters 2, 4, and 8], one in the fusiform cortex [cluster 1], and one in the anterior middle cingulate cortex [cluster 6]). Other handedness-associated asymmetry clusters were not significantly heritable, including the pre- and postcentral clusters of the sensorimotor cortex (clusters 7 and 10). The associations of cortical asymmetries with polygenic disposition to left-handedness are indicated, as well as individual handedness-associated genes implicated in their variabilities.