DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity
Joseph H. Callicott, … , Guo-li Ming, Daniel R. Weinberger
Joseph H. Callicott, … , Guo-li Ming, Daniel R. Weinberger
Published June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):2961-2964. https://doi.org/10.1172/JCI67510.
View: Text | PDF
Brief Report Neuroscience

DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity

Abstract

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.

Authors

Joseph H. Callicott, Emer L. Feighery, Venkata S. Mattay, Michael G. White, Qiang Chen, David A.A. Baranger, Karen F. Berman, Bai Lu, Hongjun Song, Guo-li Ming, Daniel R. Weinberger

×

Figure 2

DISC1 and SLC12A2 interaction negatively impacts hippocampal connectivity.

Options: View larger image (or click on image) Download as PowerPoint
DISC1 and SLC12A2 interaction negatively impacts hippocampal connectivit...
Using PPI using a seed within the left hippocampus, we found reduced connectivity with right VLPFC in both discovery (red, n = 229) and replication (blue, n = 120) samples for DISC1 and SLC12A2 minor allele carriers (P < 0.05 FDR for both). Replication results significantly and precisely fell within regions from the discovery sample based upon an ROI created from discovery results. Heat maps correspond to statistical t values in connectivity and are displayed at P < 0.01 uncorrected. The graph depicts parameter estimate extracted from the peak difference in connectivity from the discovery sample (mean ± SEM). Numbers in the graph bars indicate the number of subjects per group.