Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

Abstract

Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations in the Korean population. Gene-based rare variants were analyzed to investigate the association between the genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect.

Fig. 1. Mutational landscape of the major depressive disorder (MDD) group.

The left-side plot displays mutated MDD-related genes (rows) across patients with MDD (columns), featuring the 40 genes from the 44 MDD-related genes based on mutation frequency across patients. Four out of the 44 MDD-related genes were not identified in our MDD patients. On the right side, a bar plot shows the number of mutated patients in the MDD group. Percentages indicate the proportion of patients with an identified mutation in each gene. The stacked bar plot on the bottom shows the distribution of the single nucleotide variants classified into six transition and transversion events for each sample. “Multi-Hit” denotes that more than one mutation was detected in a gene within one patient.

Fig. 2. Recurrent copy number alterations (CNAs).

a Recurrent focal amplified regions (red line) and b deleted regions (blue line) detected by GISTIC 2.0 analysis in 367 patients with major depressive disorder (MDD) and 161 healthy controls. The horizontal axis represents the q-value and the vertical axis represents the chromosome number. MDD-related genes are highlighted in bold-face. The green lines represent the threshold for significance (q-value < 0.25).