Molecular Neurobiology

, Volume 53, Issue 9, pp 6355–6361 | Cite as

Left-Right Axis Differentiation and Functional Lateralization: a Haplotype in the Methyltransferase Encoding Gene SETDB2 Might Mediate Handedness in Healthy Adults

  • Sebastian Ocklenburg
  • Larissa Arning
  • Wanda M. Gerding
  • Jan G. Hengstler
  • Jörg T. Epplen
  • Onur Güntürkün
  • Christian Beste
  • Denis A. Akkad


Handedness is a multifactorial trait, and genes contributing to the differentiation of the left-right axis during embryogenesis have been identified as a major gene group associated with this trait. The methyltransferase SETDB2 (SET domain, bifurcated 2) has been shown to regulate structural left-right asymmetry in the vertebrate central nervous system by suppressing fgf8 expression. Here, we investigated the relation of genetic variation in SETDB2—and its paralogue SETDB1—with different handedness phenotypes in 950 healthy adult participants. We identified a haplotype on SETDB2 for which homozygous individuals showed a significantly lower lateralization quotient for handedness than the rest of the cohort after correction for multiple comparisons. Moreover, direction of handedness was significantly associated with genetic variation in this haplotype. This effect was mainly, but not exclusively, driven by the sequence variation rs4942830, as individuals homozygous for the A allele of this single nucleotide polymorphism had a significantly lower lateralization quotient than individuals with at least one T allele. These findings further confirm a role of genetic pathways relevant for structural left-right axis differentiation for functional lateralization. Moreover, as the protein encoded by SETDB2 regulates gene expression epigenetically by histone H3 methylation, our findings highlight the importance of investigating the role of epigenetic modulations of gene expression in relation to handedness.


Genetic association study SNP Laterality Lateralization Direction of lateralization Cerebral asymmetries Ontogenesis 


Compliance with Ethical Standards

Ethical Approval

All participants gave written informed consent and were treated in accordance with the declaration of Helsinki. The study was approved by the ethics committee, Ruhr-University Bochum, Germany.


  1. 1.
    Ströckens F, Güntürkün O, Ocklenburg S (2013) Limb preferences in non-human vertebrates. Laterality 18:536–575CrossRefPubMedGoogle Scholar
  2. 2.
    Brandler WM, Paracchini S (2014) The genetic relationship between handedness and neurodevelopmental disorders. Trends Mol Med 20:83–90CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    MacNeilage PF (2014) Evolution of the strongest vertebrate rightward action asymmetries: marine mammal sidedness and human handedness. Psychol Bull 140:587–609CrossRefPubMedGoogle Scholar
  4. 4.
    Somers M, Shields LS, Boks MP, Kahn RS, Sommer IE (2015) Cognitive benefits of right-handedness: a meta-analysis. Neurosci Biobehav Rev 51:48–63CrossRefPubMedGoogle Scholar
  5. 5.
    Versace E, Vallortigara G (2015) Forelimb preferences in human beings and other species: multiple models for testing hypotheses on lateralization. Front Psychol 6:233CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Willems RM, Van der Haegen L, Fisher SE, Francks C (2014) On the other hand: including left-handers in cognitive neuroscience and neurogenetics. Nat Rev Neurosci 15:193–201CrossRefPubMedGoogle Scholar
  7. 7.
    Carter-Saltzman L (1980) Biological and sociocultural effects on handedness: comparison between biological and adoptive families. Science 209:1263–1265CrossRefPubMedGoogle Scholar
  8. 8.
    Ooki S (2014) An overview of human handedness in twins. Front Psychol 5:10CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Annett M (1996) In defence of the right shift theory. Percept Mot Skills 82:115–137CrossRefPubMedGoogle Scholar
  10. 10.
    Armour JA, Davison A, McManus IC (2014) Genome-wide association study of handedness excludes simple genetic models. Heredity 112:221–225CrossRefPubMedGoogle Scholar
  11. 11.
    McManus IC, Davison A, Armour JA (2013) Multilocus genetic models of handedness closely resemble single-locus models in explaining family data and are compatible with genome-wide association studies. Ann N Y Acad Sci 1288:48–58CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ocklenburg S, Beste C, Arning L, Peterburs J, Güntürkün O (2014) The ontogenesis of language lateralization and its relation to handedness. Neurosci Biobehav Rev 43:191–198CrossRefPubMedGoogle Scholar
  13. 13.
    Ocklenburg S, Beste C, Güntürkün O (2013) Handedness: a neurogenetic shift of perspective. Neurosci Biobehav Rev 37:2788–2793CrossRefPubMedGoogle Scholar
  14. 14.
    Rentería ME (2012) Cerebral asymmetry: a quantitative, multifactorial, and plastic brain phenotype. Twin Res Hum Genet 15:401–413CrossRefPubMedGoogle Scholar
  15. 15.
    Arning L, Ocklenburg S, Schulz S, Ness V, Gerding WM, Hengstler JG, Falkenstein M, Epplen JT et al (2013) PCSK6 VNTR polymorphism is associated with degree of handedness but not direction of handedness. PLoS One 8:e67251CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, Timpson NJ, St Pourcain B, Smith GD et al (2013) Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genet 9:e1003751CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Scerri TS, Brandler WM, Paracchini S, Morris AP, Ring SM, Richardson AJ, Talcott JB, Stein J et al (2011) PCSK6 is associated with handedness in individuals with dyslexia. Hum Mol Genet 20:608–614CrossRefPubMedGoogle Scholar
  18. 18.
    Schier AF, Shen MM (2000) Nodal signalling in vertebrate development. Nature 403:385–389CrossRefPubMedGoogle Scholar
  19. 19.
    Komatsu Y, Mishina Y (2013) Establishment of left-right asymmetry in vertebrate development: the node in mouse embryos. Cell Mol Life Sci 70:4659–4666CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hamada H, Meno C, Watanabe D, Saijoh Y (2002) Establishment of vertebrate left-right asymmetry. Nat Rev Genet 3:103–113CrossRefPubMedGoogle Scholar
  21. 21.
    Regan JC, Concha ML, Roussigne M, Russell C, Wilson SW (2009) An Fgf8-dependent bistable cell migratory event establishes CNS asymmetry. Neuron 61:27–34CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R, Edser P, Bhattacharyya S et al (2003) Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 34:181–186CrossRefPubMedGoogle Scholar
  23. 23.
    Golebiewska A, Atkinson SP, Lako M, Armstrong L (2009) Epigenetic landscaping during hESC differentiation to neural cells. Stem Cells 27:1298–1308CrossRefPubMedGoogle Scholar
  24. 24.
    Hirabayashi Y, Gotoh Y (2010) Epigenetic control of neural precursor cell fate during development. Nat Rev Neurosci 11:377–388CrossRefPubMedGoogle Scholar
  25. 25.
    Xu PF, Zhu KY, Jin Y, Chen Y, Sun XJ, Deng M, Chen SJ, Chen Z et al (2010) Setdb2 restricts dorsal organizer territory and regulates left-right asymmetry through suppressing fgf8 activity. Proc Natl Acad Sci U S A 107:2521–2526CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hervé PY, Crivello F, Perchey G, Mazoyer B, Tzourio-Mazoyer N (2006) Handedness and cerebral anatomical asymmetries in young adult males. NeuroImage 29:1066–1079CrossRefPubMedGoogle Scholar
  27. 27.
    Akkad DA, Gerding WM, Gasser RB, Epplen JT (2015) Homozygosity mapping and sequencing identify two genes that might contribute to pointing behavior in hunting dogs. Canine Genet Epidemiol 2:5CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ocklenburg S, Beste C, Arning L (2014) Handedness genetics: considering the phenotype. Front Psychol 5:1300PubMedPubMedCentralGoogle Scholar
  29. 29.
    Lien YJ, Chen WJ, Hsiao PC, Tsuang HC (2015) Estimation of heritability for varied indexes of handedness. Laterality 20:469–482CrossRefPubMedGoogle Scholar
  30. 30.
    Arning L, Ocklenburg S, Schulz S, Ness V, Gerding WM, Hengstler JG, Falkenstein M, Epplen JT et al (2015) Handedness and the X chromosome: the role of androgen receptor CAG-repeat length. Sci Rep 5:8325CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Concha ML, Burdine RD, Russell C, Schier AF, Wilson SW (2000) A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28:399–409CrossRefPubMedGoogle Scholar
  32. 32.
    Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113CrossRefPubMedGoogle Scholar
  33. 33.
    Peters M, Reimers S, Manning JT (2006) Hand preference for writing and associations with selected demographic and behavioral variables in 255,100 subjects: the BBC internet study. Brain Cogn 62:177–189CrossRefPubMedGoogle Scholar
  34. 34.
    Hirnstein M, Hugdahl K, Hausmann M (2014) How brain asymmetry relates to performance—a large-scale dichotic listening study. Front Psychol 4:997CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ocklenburg S, Güntürkün O, Beste C (2011) Lateralized neural mechanisms underlying the modulation of response inhibition processes. NeuroImage 55:1771–1778CrossRefPubMedGoogle Scholar
  36. 36.
    Onal-Hartmann C, Pauli P, Ocklenburg S, Güntürkün O (2012) The motor side of emotions: investigating the relationship between hemispheres, motor reactions and emotional stimuli. Psychol Res 76:311–316CrossRefPubMedGoogle Scholar
  37. 37.
    De Winter FL, Zhu Q, Van den Stock J, Nelissen K, Peeters R, de Gelder B, Vanduffel W, Vandenbulcke M (2015) Lateralization for dynamic facial expressions in human superior temporal sulcus. NeuroImage 106:340–352CrossRefPubMedGoogle Scholar
  38. 38.
    Vogel JJ, Bowers CA, Vogel DS (2003) Cerebral lateralization of spatial abilities: a meta-analysis. Brain Cogn 52:197–204CrossRefPubMedGoogle Scholar
  39. 39.
    Ocklenburg S, Rüther N, Peterburs J, Pinnow M, Güntürkün O (2011) Laterality in the rubber hand illusion. Laterality 16:174–187CrossRefPubMedGoogle Scholar
  40. 40.
    Hampson E, Sankar JS (2012) Hand preference in humans is associated with testosterone levels and androgen receptor gene polymorphism. Neuropsychologia 50:2018–2025CrossRefPubMedGoogle Scholar
  41. 41.
    Medland SE, Duffy DL, Spurdle AB, Wright MJ, Geffen GM, Montgomery GW, Martin NG (2005) Opposite effects of androgen receptor CAG repeat length on increased risk of left-handedness in males and females. Behav Genet 35:735–744CrossRefPubMedGoogle Scholar
  42. 42.
    Francks C, Maegawa S, Laurén J, Abrahams BS, Velayos-Baeza A, Medland SE, Colella S, Groszer M et al (2007) LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. Mol Psychiatry 12:1129–1139CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Leach EL, Prefontaine G, Hurd PL, Crespi BJ (2014) The imprinted gene LRRTM1 mediates schizotypy and handedness in a nonclinical population. J Hum Genet 59:332–336CrossRefPubMedGoogle Scholar
  44. 44.
    Somers M, Ophoff RA, Aukes MF, Cantor RM, Boks MP, Dauwan M, de Visser KL, Kahn RS et al (2015) Linkage analysis in a Dutch population isolate shows no major gene for left-handedness or atypical language lateralization. J Neurosci 35:8730–8736CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B, Saxonov S, Avey L, Wojcicki A et al (2010) Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet 6:e1000993CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Massari ME, Murre C (2000) Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20:429–440CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Scharoun SM, Bryden PJ (2014) Hand preference, performance abilities, and hand selection in children. Front Psychol 5:82CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Medland SE, Duffy DL, Wright MJ, Geffen GM, Hay DA, Levy F, van-Beijsterveldt CE, Willemsen G et al (2009) Genetic influences on handedness: data from 25,732 Australian and Dutch twin families. Neuropsychologia 47:330–337CrossRefPubMedGoogle Scholar
  49. 49.
    Ocklenburg S, Bürger C, Westermann C, Schneider D, Biedermann H, Güntürkün O (2010) Visual experience affects handedness. Behav Brain Res 207:447–451CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sebastian Ocklenburg
    • 1
  • Larissa Arning
    • 2
  • Wanda M. Gerding
    • 2
  • Jan G. Hengstler
    • 3
  • Jörg T. Epplen
    • 2
    • 4
  • Onur Güntürkün
    • 1
  • Christian Beste
    • 5
  • Denis A. Akkad
    • 2
  1. 1.Institute of Cognitive Neuroscience, Biopsychology, Department of PsychologyRuhr-UniversityBochumGermany
  2. 2.Department of Human GeneticsRuhr-UniversityBochumGermany
  3. 3.Leibniz Research Centre for Working Environment and Human Factors (IfADo)DortmundGermany
  4. 4.Faculty of HealthUniversity Witten-HerdeckeWittenGermany
  5. 5.Cognitive Neurophysiology, Department of Child and Adolescent PsychiatryFaculty of Medicine of the TU DresdenDresdenGermany

Personalised recommendations