Effects of the LHPP gene polymorphism on the functional and structural changes of gray matter in major depressive disorder.

Background: A single-nucleotide polymorphism (SNP) of the LHPP gene (rs35936514) has been reported to be associated with major depressive disorder (MDD) in genome-wide association studies. However, the systems-level neural effects of rs35936514 that mediate the association are unknown. We hypothesized that variations in rs35936514 would be associated with structural and functional changes in gray matter (GM) at rest in MDD patients.

Methods: A total of 50 MDD patients and 113 healthy controls (HCs) were studied. Functional connectivity (FC) was analyzed by defining the bilateral hippocampus as the seed region. Voxel-based morphometry (VBM) was performed to assess the patterns of GM volume. The subjects were further divided into two groups: a CC homozygous group (CC; 24 MDD and 56 HC) and a risk T-allele carrier group (CT/TT genotypes; 26 MDD and 57 HC). A 2×2 analysis of variance (ANOVA: diagnosis × genotype) was used to determine the interaction effects and main effect (P<0.05).

Results: Significant diagnosis × genotype interaction effects on brain morphology and FC were noted. Compared to other subgroups, the MDD patients with the T allele showed an increased hippocampal FC in the bilateral calcarine cortex and cuneus and a decreased hippocampal FC in the right dorsolateral prefrontal cortex (DLPFC), bilateral anterior cingulate cortex (ACC), and medial prefrontal cortex (MPFC), in addition to reduced GM volume in the right DLPFC, bilateral temporal cortex, and posterior cingulate cortex (PCC).

Conclusions: LHPP gene polymorphisms may affect functional and structural changes in the GM at rest and may play an important role in the pathophysiological mechanisms of MDD.