Genetic underpinnings of cerebral edema in acute brain injury: an opportunity for pathway discovery

Neurosci Lett. 2020 Jun 21:730:135046. doi: 10.1016/j.neulet.2020.135046. Epub 2020 May 26.


Cerebral edema constitutes an important contributor to secondary injury in acute brain injury. The quantification of cerebral edema in neuroimaging, a well-established biomarker of secondary brain injury, represents a useful intermediate phenotype to study edema formation. Population genetics provides powerful tools to identify novel susceptibility genes, biological pathways and therapeutic targets related to brain edema formation. Here, we provide an overview of the pathogenesis of cerebral edema, introduce relevant genetic methods to study this process, and discuss the ongoing research on the genetic underpinnings of edema formation in acute brain injury. The epsilon 2 and 4 variants within the Apolipoprotein E (APOE) gene are associated with worse outcome after traumatic brain injury and intracerebral hemorrhage, and recent studies link these polymorphisms to inflammatory processes that lead to blood-brain barrier disruption and vasogenic edema. For the Haptoglobin gene (HP), the Hp 2-2 genotype associates with worse outcome after acute brain injury, whereas the haptoglobin Hp 1-1 genotype correlates with increased edema in the early phases of intracerebral hemorrhage. Another important protein in cerebral edema is aquaporin 4, coded by the AQP4 gene. AQP4 mutations contribute to the formation of cytotoxic edema, and further genetic research is necessary to help elucidate the mediating mechanism. Findings supporting the target genes outlined above require replication in larger samples and evaluation in non-white populations. These next steps will be significantly facilitated by the rapid changes observed in the field of population genetics, including large international collaborations, open access to genetic data, and significant reductions in the cost of genotyping technologies.

Keywords: Brain edema; Hemorrhagic stroke; Intracerebral hemorrhage; Ischemic stroke; Stroke; Stroke genetics; Traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Aquaporin 4 / metabolism
  • Brain Edema / genetics*
  • Brain Edema / pathology
  • Brain Edema / physiopathology
  • Brain Injuries / complications
  • Brain Injuries / genetics*
  • Brain Injuries / physiopathology
  • Brain Ischemia / drug therapy
  • Brain Ischemia / genetics*
  • Humans
  • Neuroimaging / methods
  • Stroke / genetics*
  • Stroke / pathology


  • Aquaporin 4