title: Left-Right Axis Differentiation and Functional Lateralization: a Haplotype in the Methyltransferase Encoding Gene SETDB2 Might Mediate Handedness in Healthy Adults.
abstract: 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.
authors.affiliation: Institute of Cognitive Neuroscience, Biopsychology, Department of Psychology, Ruhr-University, 44780, Bochum, Germany. sebastian.ocklenburg@rub.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ocklenburg
authors.affiliation: Department of Human Genetics, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Arning
authors.affiliation: Department of Human Genetics, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Gerding
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139, Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Department of Human Genetics, Ruhr-University, 44780, Bochum, Germany.|Faculty of Health, University Witten-Herdecke, 58448, Witten, Germany.
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Epplen
authors.affiliation: Institute of Cognitive Neuroscience, Biopsychology, Department of Psychology, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Onur
authors.initials: O
authors.lastname: Güntürkün
authors.affiliation: Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, 01309, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beste
authors.affiliation: Department of Human Genetics, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019521:Body Patterning / Q000235:genetics*; D005260:Female; D007839:Functional Laterality / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C000625967:SETDB2 protein, human
keywords: Cerebral asymmetries; Direction of lateralization; Genetic association study; Laterality; Lateralization; Ontogenesis; SNP