Handedness, Language Areas and Neuropsychiatric Diseases

Insights From Brain Imaging and Genetics

Akira Wiberg; Michael Ng; Yasser Al Omran; Fidel Alfaro-Almagro; Paul McCarthy; Jonathan Marchini; David L. Bennett; Stephen Smith; Gwenaëlle Douaud; Dominic Furniss


Brain. 2019;142(10):2938-2947. 

In This Article

Abstract and Introduction


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.


One of the most remarkable features of human motor control is that ~90% of the population has had a preference for using their right hand over the left since at least the Paleolithic period (Faurie and Raymond, 2004), and this skew in distribution of handedness is a uniquely human trait. It is widely believed that the lateralization of language in the left hemisphere accounts for the evolution of right-handedness in the majority of humans (Corballis, 2003). There are well-established associations between left-handedness and several neurodevelopmental disorders (Brandler and Paracchini, 2014); in particular, a meta-analysis of 50 studies concluded that non-right-handedness was significantly more common in participants with schizophrenia [odd ratio (OR) = 1.55, 95% confidence interval (CI) 1.25–1.93] (Hirnstein and Hugdahl, 2014).

Neuroanatomical studies of human handedness have been equivocal, most likely owing to small- to medium-sized study populations (Hatta, 2007; Guadalupe et al., 2014). While studies dedicated to one specific cortical feature, such as the shape and depth of the central sulcus (Amunts et al., 1996; Sun et al., 2012), or the gyrification pattern of Heschl's gyrus (Marie et al., 2015), have shown differences in left-handers, no significant cortical area correlates of handedness were found in the largest study sample so far (106 left-handed subjects, 1960 right-handed subjects) (Guadalupe et al., 2014). Functional imaging in the motor cortex has largely been inconclusive (Hatta, 2007). Conversely, differences in the lateralization pattern of language function have been consistently observed, with left-handers showing more bilateral or right-hemispheric language activation (Tzourio et al., 1998; Pujol et al., 1999; Knecht, 2002; Joliot et al., 2016).

Another unresolved issue is whether such a population bias in handedness is under genetic influence. While left-handedness runs in families (Medland et al., 2009), and concordance of handedness is greater in monozygotic twins than dizygotic twins, with an estimated heritability of 25% (Medland et al., 2006), significantly associated loci for human handedness in the general population have thus far remained elusive (Eriksson et al., 2010).

UK Biobank is a prospective cohort study of ~500 000 participants who have allowed linkage of their physical data, including genetics, with their medical records, lifestyle questionnaires, and cognitive measures. An imaging extension includes six distinct modalities covering structural, diffusion and functional imaging of the brain, with an automatic pipeline generating thousands of image-derived phenotypes (IDPs), which are distinct individual measures that can be used for correlation with other phenotypes, or for genetic analysis (Miller et al., 2016; Alfaro-Almagro et al., 2018; Elliott et al., 2018).

Using imaging, genotype and handedness data from UK Biobank, we aimed to discover correlations between: (i) handedness phenotype and IDPs; (ii) genotype and handedness; and (iii) handedness-related genotypes and IDPs. Supplementary Figure 1 summarizes the key findings from the three arms of this study.

Supplementary Figure 1.

Summary of results from the genetics-handedness, genetics-brain imaging, and handedness-brain imaging studies.