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.
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
Arcuate Fasciculus Asymmetry Has a Hand in Language Function but Not HandednessJB Allendorfer et al. Hum Brain Mapp 37 (9), 3297-309. PMID 27144738.The importance of relationships between handedness, language lateralization and localization, and white matter tracts for language performance is unclear. The goal of the …
Fiber Density Asymmetry of the Arcuate Fasciculus in Relation to Functional Hemispheric Language Lateralization in Both Right- And Left-Handed Healthy Subjects: A Combined fMRI and DTI StudyMW Vernooij et al. Neuroimage 35 (3), 1064-76. PMID 17320414.Previously reported leftward asymmetry in language-related gray and white matter areas of the brain has been proposed as a structural correlate of left-sided functional h …
The Functional Genetics of Handedness and Language Lateralization: Insights From Gene Ontology, Pathway and Disease Association AnalysesJ Schmitz et al. Front Psychol 8, 1144. PMID 28729848.Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting …
Genetic Underpinnings of White Matter 'Connectivity': Heritability, Risk, and Heterogeneity in SchizophreniaAN Voineskos. Schizophr Res 161 (1), 50-60. PMID 24893906. - ReviewSchizophrenia is a highly heritable disorder. Thus, the combination of genetics and brain imaging may be a useful strategy to investigate the effects of risk genes on ana …
Intra- And Inter-hemispheric Connectivity Supporting Hemispheric SpecializationN Tzourio-Mazoyer. None 129-146. PMID 28590670. - ReviewHemispheric specialization (HS), or hemispheric dominance, is a nineteenth century concept that relates to the fact that a given hemisphere is the pilot of a given functi …
- Amunts K, Schlaug G, Schleicher A, Steinmetz H, Dabringhaus A, Roland PE et al. Asymmetry in the human motor cortex and handedness. Neuroimage 1996; 4: 216–222. - PubMed
- Behrens TEJ, Woolrich MW, Jenkinson M, Johansen-Berg H, Nunes RG, Clare S et al. Characterization and propagation of uncertainty in diffusion-weighted MR imaging. Magn Reson Med 2003; 50: 1077–88. - PubMed
- Berlim MT, Mattevi BS, Belmonte-de-Abreu P, Crow TJ. The etiology of schizophrenia and the origin of language: overview of a theory. Compr Psychiatry 2003; 44: 7–14. - PubMed
- 202747/Wellcome Trust/United Kingdom
- 097152/Wellcome Trust/United Kingdom
- MR/N001524/1/Medical Research Council/United Kingdom
- 098369/Wellcome Trust/United Kingdom
- MR/K006673/1/Medical Research Council/United Kingdom