Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology

Biol Psychiatry. 2021 Nov 1;90(9):652-660. doi: 10.1016/j.biopsych.2021.06.021. Epub 2021 Jul 7.


Background: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology.

Methods: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [18F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS).

Results: Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO.

Conclusions: This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.

Keywords: C4A; Hippocampal morphology; Microglial function; Translocator protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / diagnostic imaging
  • Brain / metabolism
  • Hippocampus / diagnostic imaging
  • Hippocampus / metabolism
  • Humans
  • Microglia / metabolism
  • Positron-Emission Tomography
  • Psychotic Disorders*
  • Pyridines
  • Receptors, GABA* / genetics
  • Receptors, GABA* / metabolism


  • Pyridines
  • Receptors, GABA
  • TSPO protein, human