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PreprintCited by 27Hemispheric Asymmetry in NeuroscienceGenetic Associations and EpidemiologyGenetics and Neurodevelopmental Disorders

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Exome-wide analysis implicates rare protein-altering variants in human handedness

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Schijven, Dick, Soheili-Nezhad, Sourena, Fisher, Simon E., Francks, Clyde·2023·Nature Communications
DOI 10.1101/2023.05.31.543042PMC PMC10987538

Preprint — published as 10.1038/s41467-024-46277-w · Paper page

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Abstract

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examined whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals (UK Biobank). The beta-tubulin gene TUBB4B showed exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers (0.076%) than right-handers (0.028%). The TUBB4B variants were mostly heterozygous missense changes, but included two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 showed evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study revealed a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

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Metadata

Authors
Schijven, D., Soheili-Nezhad, S., Fisher, S. E., & Francks, C.
Affiliations
Radboud University Nijmegen (NL)
Corresponding author
Francks, Clyde
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2023-06-01
Volume
15
Issue
1
Pages
2632-2632
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2023.05.31.543042
PMC
PMC10987538
OpenAlex
W4393549112
Cited by
27
References
1
Citations by year
2026: 7 · 2025: 10 · 2024: 10
FWCI
6.56
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.001.006)
  • Max-Planck-Gesellschaft
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Hemispheric Asymmetry in Neuroscience
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
left-handedness, handedness, beta-tubulin, microtubules, Dscam, FOXP1, exome-wide association, heritability, neurodevelopmental disorders, autism spectrum disorder, schizophrenia
MeSH terms
Brain, Humans, Functional Laterality, Repressor Proteins, Forkhead Transcription Factors, Genome-Wide Association Study, Exome

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