Neural Mechanisms of a Genome-Wide Supported Psychosis Variant

Abstract

Schizophrenia is a devastating, highly heritable brain disorder of unknown etiology. Recently, the first common genetic variant associated on a genome-wide level with schizophrenia and possibly bipolar disorder was discovered in ZNF804A (rs1344706). We show, by using an imaging genetics approach, that healthy carriers of rs1344706 risk genotypes exhibit no changes in regional activity but pronounced gene dosage-dependent alterations in functional coupling (correlated activity) of dorsolateral prefrontal cortex (DLPFC) across hemispheres and with hippocampus, mirroring findings in patients, and abnormal coupling of amygdala. Our findings establish disturbed connectivity as a neurogenetic risk mechanism for psychosis supported by genome-wide association, show that rs1344706 or variation in linkage disequilibrium is functional in human brain, and validate the intermediate phenotype strategy in psychiatry.

Erratum: Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

“…[33][34][35] As expected, we observed significant association of rs2709370 with hippocampal function during memory recall (P<0.01, family wise error corrected for multiple comparisons across the region of interest, Figure 2). The risk allele [C] carriers likewise showed diminished activation of the left hippocampus, consistent with a previous study of patients with BD who showed impaired hippocampal function, further supporting the involvement of CREB1 in BD.…”

“…30,31 We extracted the association results of CREB1 SNP with bilateral hippocampal volume instead of single-side hippocampal volume from these two GWASs, because the volumes of the right and left hippocampus do not differ significantly in healthy subjects, 31 and the genetic bases are likely the same. 32 For brain functions, we analyzed the data of a German sample of healthy individuals (N = 279) that was part of an ongoing study on neurogenetic mechanisms of psychiatric disease to study the effects of risk CREB1 SNPs on hippocampal function, [33][34][35] using blood oxygenation level-dependent functional magnetic resonance imaging measurement during three consecutive blocks of memory tasks (that is, encoding, recall and recognition of faceprofession pairs). We analyzed the effects of the SNPs on right and left hippocampal function separately, assuming potential asymmetry in hippocampal function, with the right hippocampus supporting processes contributing to visuo-spatial memory and the left hippocampus to verbal/narrative or episodic memory.…”

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe

“…Subjects (n= 122) were drawn from an ongoing large-scale multicenter imaging genetics study 18 (Esslinger et al plus 7 subsequently scanned subjects) that is being conducted at two sites in Mannheim and Bonn, Germany. All participants were healthy German volunteers with parents and grandparents of European origin.…”

Human genetics: Hit or miss?

“…One group took 115 healthy people, a little less than half of whom had two copies of the high-risk ZNF804A variant, and compared their brain activity using functional magnetic resonance imaging (fMRI), a method that reveals local blood oxygenation and presumably electrical activity in the brain in real time. Those with the variant, they found, had abnormal connectivity between certain brain areas, impairing "the degree in which they talk to one another", says Andreas Meyer-Lindenberg, the director of the Central Institute of Mental Health in Mannheim, Germany, who led the study 6 . Healthy adults with the variant were showing schizophrenia-like brain activity even though they showed no outward signs of disease.…”