Variation in the CACNB2 gene is associated with functional connectivity of the Hippocampus in bipolar disorder

Fang Liu,Yanqing Tang,Xiaohong Gong,Fei Wang,Xudong Yao,Lingling Cui,Chao Li,Zhiyang Yin

doi:10.1186/s12888-019-2040-8

Abstract

BackgroundCalcium voltage-gated channel auxiliary subunit β2 is a protein that, in humans, is encoded by the CACNB2 gene. The β2 subunit is an auxiliary protein of voltage-gated calcium channels, which is predominantly expressed in hippocampal pyramidal neurons. A single-nucleotide polymorphism at the CACNB2 gene (rs11013860) has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural effects of rs11013860 expression are unknown. Thus, the current study investigated the mechanisms of how the CACNB2 gene influences hippocampal-cortical limbic circuits in patients with bipolar disorder (BD).MethodsA total of 202 subjects were studied [69 BD patients and 133 healthy controls (HC)]. Participants agreed to undergo resting-state functional magnetic resonance imaging (rs-fMRI) and have blood drawn for genetic testing. Participants were found to belong to either a CC group homozygous for the C-allele (17 BD, 41 HC), or an A-carrier group carrying the high risk A-allele (AA/CA genotypes; 52 BD, 92 HC). Brain activity was assessed using resting-state functional connectivity (rs-FC) analyses.ResultsA main effect of genotype showed that the rs-FC of the AA/CA group was elevated more than that of the CC-group between the hippocampus and the regions of right-inferior temporal, fusiform, and left-inferior occipital gyri. Additionally, a significant diagnosis × genotype interaction was noted between the hippocampus and right pars triangularis. Furthermore, in BD patients, the AA/CA group showed lower rs-FC when compared to that of the CC group. Additionally, individuals from HC within the AA/CA group showed higher rs-FC than that of the CC group. Finally, within C-allele-carrying groups, individuals with BD showed significantly increased rs-FC compared to that of HC.ConclusionsOur study demonstrates that BD patients with the CACNB2 rs11013860 AA/CA genotype may exhibit altered hippocampal-cortical connectivity.

Highlights

Calcium voltage-gated channel auxiliary subunit β2 is a protein that, in humans, is encoded by the CACNB2 gene
One genome-wide association (GWAS) study of bipolar disorder (BD) in the Han Chinese population found that rs11013860 in the CACNB2 gene is associated with BD-I (p = 5.15*10− 5) [6]
A separate study conducted joint analyses of four markers (CACNA1C rs10848635, CACNA1E rs10848635, CACNB2 rs11013860, and CACNG2 rs 2,284,018) and found higher accumulative risk in individuals diagnosed with BD-I and BD-II

Summary

Introduction

Calcium voltage-gated channel auxiliary subunit β2 is a protein that, in humans, is encoded by the CACNB2 gene. The β2 subunit is an auxiliary protein of voltage-gated calcium channels, which is predominantly expressed in hippocampal pyramidal neurons. A single-nucleotide polymorphism at the CACNB2 gene (rs11013860) has been reported in genome-wide association studies to be associated with bipolar disorder (BD). The current study investigated the mechanisms of how the CACNB2 gene influences hippocampal-cortical limbic circuits in patients with bipolar disorder (BD). Bipolar disorder (BD) is a relatively common mental illness. One genome-wide association (GWAS) study of BD in the Han Chinese population found that rs11013860 in the CACNB2 gene is associated with BD-I (p = 5.15*10− 5) [6]. How rs11013860 may mediate this association is unknown

Methods

Results

Conclusion