Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics

Abstract

Ninety per cent of the human population has been right-handed since the Paleolithic, yet the brain signature and genetic basis of handedness remain poorly characterized. Here, we correlated brain imaging phenotypes from ∼9000 UK Biobank participants with handedness, and with loci found significantly associated with handedness after we performed genome-wide association studies (GWAS) in ∼400 000 of these participants. Our imaging-handedness analysis revealed an increase in functional connectivity between left and right language networks in left-handers. GWAS of handedness uncovered four significant loci (rs199512, rs45608532, rs13017199, and rs3094128), three of which are in-or expression quantitative trait loci of-genes encoding proteins involved in brain development and patterning. These included microtubule-related MAP2 and MAPT, as well as WNT3 and MICB, all implicated in the pathogenesis of diseases such as Parkinson's, Alzheimer's and schizophrenia. In particular, with rs199512, we identified a common genetic influence on handedness, psychiatric phenotypes, Parkinson's disease, and the integrity of white matter tracts connecting the same language-related regions identified in the handedness-imaging analysis. This study has identified in the general population genome-wide significant loci for human handedness in, and expression quantitative trait loci of, genes associated with brain development, microtubules and patterning. We suggest that these genetic variants contribute to neurodevelopmental lateralization of brain organization, which in turn influences both the handedness phenotype and the predisposition to develop certain neurological and psychiatric diseases.

Keywords: GWAS; Parkinson’s disease; arcuate fasciculus; handedness; microtubules.

Figure 1

Language-related grey matter regions functionally involved with self-reported handedness are connected by white matter tracts associated with rs199512. (A and B) Left-handedness was most strongly associated with an increase in functional connectivity (temporal correlation) between right homologous language functional network (in green, encompassing Broca’s areas, the planum temporale and superior temporal sulcus, Z > 5), and a split of the left language functional network (in red-yellow, Broca’s areas and planum temporale shown in A, superior temporal sulcus shown in B, Z > 5). These language-related functional networks are overlaid on the cortical surface. (C) Voxelwise effects in white matter associated with rs199512 (in red, P < 3.6 × 10⁻⁷) were used as seeds for probabilistic tractography, which reconstructed the arcuate and superior longitudinal fasciculus (III) (in blue-light blue, thresholded for better visualization at 250 samples). Results are overlaid on the MNI T₁-weighted template (axial views: z = 27, 12,−3 mm; sagittal views: x = −39, 39 mm). These white matter tracts clearly link the grey matter areas present in lateralized right- and left-sided language functional networks (in green and red-yellow, respectively, also shown in A and B).

Figure 2

Summary of GWAS of handedness. (A–C) Manhattan plots showing −log10 P-values for SNP associations in GWAS of: (A) right-handers versus left-handers, (B) right-handers versus non-right-handers, and (C) left-handers versus non-left handers. Variants coloured in red have genome-wide significant associations (P = 5 × 10⁻⁸). (D–F) Regional association plots of the associated SNPs: (D) rs13017199 at 2q34, (E) rs3094128 at 6p21.33, (F) rs199512 at 17q21.31 (with a wider window to show the entirety of the MAPT region), and (G) rs45608532 at 22q11.22, where the low linkage disequilibrium relationship between the SNPs is consistent with what has previously been reported in this region on chromosome 22 (Dawson et al., 2002). The genomic positions of the SNPs and genes is based on Human Genome build hg19.