Effect of genetic variant in BICC1 on functional and structural brain changes in depression

Abstract

Genes and early-life adversity (ELA) interactively increase the risk of developing major depressive disorder (MDD). A recent genome-wide association study suggests that the minor T-allele of single-nucleotide polymorphisms in the bicaudal C homolog 1 gene (BICC1) has a protective role against MDD. The aims of the study were to investigate whether the minor T-allele of BICC1 is protective against hippocampal structural brain changes, whether it is associated with increased functional brain activity in the emotion regulation system, and how ELA would modify this association. Forty-four patients with MDD and 44 healthy controls were investigated using structural magnetic resonance imaging (MRI) and functional MRI with an emotion inhibition task. Analysis of a single-nucleotide polymorphism in the BICC1-1 (rs999845) gene was performed. Right hippocampal bodies of patients and controls without a history of ELA and who carry the protective T-allele of BICC1 were significantly larger compared with those participants homozygous for the major C-allele of BICC1. However, MDD patients with ELA, who carry the T-allele, had smaller hippocampal head volumes compared with MDD patients without ELA. FMRI showed that patients and controls carrying the protective T-allele of BICC1 activate the emotion regulation system significantly more compared with those participants homozygous for the major C-allele (p<0.05, family wise error corrected). These results are suggestive that the minor T-allele of BICC1 has a protective role against MDD and its known structural and functional brain changes. However, this protective effect seems to be lost in the case of co-occurrence of ELA.

Figure 1

Smaller hippocampal head volumes, left and right, in patients with major depressive disorder (MDD) and early-life adversity (ELA), when they carry the T-allele of BICC1 compared with when they are homozygous for the C-allele. Larger right hippocampal head volumes in those patients carrying the T-allele of BICC1 when they do not have ELA compared with those with the same genotype when they have a history of ELA.

Figure 2

Larger right hippocampal head volumes in those subjects carrying the T-allele of BICC1 when they do not have early-life adversity (ELA) compared with those homozygous for the C-allele when they have a history and also when they do not have a history of ELA. Sidak corrected values. Values inset indicate number of subjects in each group.

Figure 3

Positive stimuli. Axial slice presenting areas statistically significant for: (a) the interaction between diagnosis × BICC1, (b) differences in patients neural activity between minor T-allele carriers compared with homozygous C-allele carriers, and (c) differences in patients neural activity between minor T-allele carriers without ELA compared with homozygous C-allele carriers without ELA. The bar under the picture presents T values scale with the values matching colors representing activation. All significance is on the level of p<0.05 after whole-brain voxel family wise error correction.