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DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity.

Joseph H Callicott1, Emer L Feighery, Venkata S Mattay

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Summary
This summary is machine-generated.

Genetic risk alleles in DISC1 and SLC12A2 interact to impair hippocampal function in healthy individuals, impacting brain activation and connectivity during memory tasks.

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Area of Science:

  • Neuroscience
  • Genetics
  • Psychiatry

Background:

  • Hippocampal development relies on extracellular factors like GABA neurotransmission and intracellular proteins like DISC1.
  • Previous research linked SLC12A2-dependent GABA depolarization and DISC1 to hippocampal development.
  • Two single nucleotide polymorphisms (SNPs) in these genes interactively increase schizophrenia risk.

Purpose of the Study:

  • To investigate the in vivo biological interaction of specific genetic risk variants in DISC1 and SLC12A2.
  • To examine the impact of these interacting variants on hippocampal function during a recognition memory task.

Main Methods:

  • Functional magnetic resonance imaging (fMRI) was used in two independent samples of healthy individuals (N=349).
  • Participants were genotyped for two risk alleles in DISC1 and SLC12A2.
  • fMRI data analyzed hippocampal area activation and connectivity during a recognition memory task.

Main Results:

  • Subjects homozygous for both risk alleles showed significantly decreased hippocampal area activation (Cohen's d = 0.78).
  • These subjects also exhibited reduced hippocampal connectivity (d = 0.57).
  • The findings confirm a biological interaction between the risk alleles in vivo.

Conclusions:

  • Epistatic models are crucial for understanding the genetic basis of complex brain phenotypes.
  • Interactions between DISC1 and SLC12A2 risk variants affect hippocampal function relevant to brain disorders.
  • This study provides in vivo evidence for gene-gene interactions influencing brain structure and function.