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Publications

Journal Article Epublish

PubMed: 42730919 DOI: 10.1007/s00415-026-14139-8

Investigating genetic susceptibility to concussion through rare variants in ion channel and neurotransmission genes.

J Neurol 273(10)

Authors: Bridget H Maher, Neven Maksemous, Heidi G Sutherland, Robert A Smith, Omar Dabash, Annette Greenhow, Fatima A Nasralla, Dale R Nyholt, Arn M J M van den Maagdenberg, Rodney A Lea, Lyn R Griffiths

Affiliations

  • Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
  • Faculty of Law, Bond University, Gold Coast, QLD, Australia.
  • Queensland Brain Institute, University of Queensland, St Lucia, QLD, 4072, Australia.
  • Statistical and Genomic Epidemiology Laboratory, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
  • Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
  • Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
  • Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.

Abstract

Some individuals appear more susceptible to concussion or mild traumatic brain injury (mTBI) and the severity, range, and the persistence of post-concussion symptoms vary considerably between affected individuals. Genetic factors are likely to contribute to this variability. Symptomatic overlap of post-concussion syndrome with neurological conditions such as familial hemiplegic migraine (FHM) caused by rare pathogenic variants in ion channel and synapse protein genes, with high sensitivity to head trauma for some patients, suggests that variation in similar pathways may influence concussion susceptibility and recovery. To investigate this hypothesis, we performed whole exome sequencing in 93 unrelated individuals who had sustained a single or multiple concussions and examined rare protein-altering variants in FHM genes, other neuronal ion channel and transporter genes, and genes involved in neurotransmission. We identified 62 different rare missense variants across 24 genes in 59 participants (63%), with 26 individuals carrying 2 or more variants. The prevalence of specific likely damaging rare variants in the 16 ion channel-related genes that were identified was approximately fivefold higher than that observed from gnomAD population controls (Odds Ratio = 5.44, 95% CI [4.13,7.18], P < 0.0001). Notably, voltage-gated calcium and sodium channel genes, including SCN9A, together with neurotransmission-related genes such as SNCAIP, harboured multiple potentially deleterious variants. These findings suggest that rare deleterious variants in genes involved in ion homeostasis and neurotransmission may contribute to an individual's susceptibility to concussion or more severe post-concussion symptoms. This study provides a foundation for future genetic and functional investigations aimed at improving our understanding of concussion susceptibility and outcomes. Further validation in larger cohorts and mechanistic studies is warranted to determine their utility as biomarkers of concussion risk and prognosis.

MeSH

Genes, Genetic Predisposition To Disease, Neurosurgery, Signs And Symptoms, Ion Channels, Wounds And Injuries, Neurology, Synaptic Transmission, Post-Concussion Syndrome