DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity.
Hippocampal development is coordinated by both extracellular factors like GABA neurotransmission and intracellular components like DISC1. We previously reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and 2 SNPs in these genes linked to mRNA expression interactively increase schizophrenia risk. Using functional MRI, we now confirm this biological interaction in vivo by showing in 2 independent samples of healthy individuals (total N = 349) that subjects homozygous for both risk alleles evince dramatically decreased hippocampal area activation (Cohen's d = 0.78)and connectivity (d = 0.57) during a recognition memory task. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes.
Clinical Brain Disorders Branch, Division of Intramural Programs, National Institute of Mental Health, NIH, Bethesda, Maryland 20892-1379, USA. callicottj@mail.nih.gov
Joseph H
JH
Callicott
Emer L
EL
Feighery
Venkata S
VS
Mattay
Michael G
MG
White
Qiang
Q
Chen
David A A
DA
Baranger
Karen F
KF
Berman
Bai
B
Lu
Hongjun
H
Song
Guo-li
GL
Ming
Daniel R
DR
Weinberger
D000293:Adolescent; D000328:Adult; D063132:Connectome; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020534:Parahippocampal Gyrus / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics* / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D055815:Young Adult
C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; C578877:SLC12A2 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2