Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity

Abstract

Background: Genome-wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto-hippocampal connectivity.

Methods: We used functional magnetic resonance imaging to measure neural activation during an n-back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working-memory-related DLPFC activation and functional integration using a seed region functional connectivity approach.

Results: Rs1006737 genotype was associated with altered right-hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G-allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto-hippocampal connectivity with rs1006737 A alleles.

Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype-related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder.

Keywords: CACNA1C; prefrontal connectivity; rs1006737; schizophrenia; working memory.

Figure 1

Effect of the rs1006737 genotype on working‐memory‐related neural activation in the prefrontal cortex. A. Results of a two‐sample t‐test comparing working‐memory‐related activation (2‐back > 0‐back) in G‐allele carriers with A homozygotes ([GG + GA] > 2AA) rendered on an individual surface image. Displayed results are controlled for participants sex and thresholded at t(91) > 3.18, P < 0.001, uncorrected, k = 216–1.73 cm³. B. Average parameter estimates for the contrast 2‐back > 0‐back of the significant DLPFC cluster are shown for the three rs1006737 genotype groups (GG, GA, and AA), indicating that the group homozygous for the A allele has significantly less activation than the other groups. C. Differences in measured signal between 2‐back and 0‐back at the resolution of one TR within the significant cluster. Average parameter estimates are extracted within the cluster at (54, 10, 38 mm) for a finite impulse response model and plotted for each rs1006737 genotype group separately with the standard error. From left to right, the first dark‐grey shaded area indicates the instruction period for the 2‐back and 0‐back condition, followed by the light‐grey shaded 0‐back and 2‐back condition. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Effects of rs1006737 genotype on prefrontal‐hippocampal functional connectivity. A. Genetic risk‐dependent altered functional connectivity with the right dorsolateral prefrontal cortex (DLPFC) time series in both hippocampal formations (HFs). Sagittal slides illustrate the results of a random‐effects analysis in an additive genetic model (GG < GA < AA) controlling for participants' sex and seed time series location, thresholded at t(87) > 3.19, P < 0.001, uncorrected. B. Connectivity parameters with the right DLPFC seed time series in the left HF (gray columns) and right HF (white columns). Individual β‐parameters were averaged within the significant clusters and plotted together with the mean and standard error for each level of rs1006737 genotype after controlling for sex and the seed time series location. Numbers in brackets denote MNI coordinates for the peak voxel of the corresponding cluster. C. Increase of functional connectivity with number of A alleles in the parahippocampal cortex, thresholded at t(87) > 3.19, P < 0.001, uncorrected, k = 470. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]