A joint study of whole exome sequencing and structural MRI analysis in major depressive disorder

Psychol Med. 2020 Feb;50(3):384-395. doi: 10.1017/S0033291719000072. Epub 2019 Feb 6.

Abstract

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide and influenced by both environmental and genetic factors. Genetic studies of MDD have focused on common variants and have been constrained by the heterogeneity of clinical symptoms.

Methods: We sequenced the exome of 77 cases and 245 controls of Han Chinese ancestry and scanned their brain. Burden tests of rare variants were performed first to explore the association between genes/pathways and MDD. Secondly, parallel Independent Component Analysis was conducted to investigate genetic underpinnings of gray matter volume (GMV) changes of MDD.

Results: Two genes (CSMD1, p = 5.32×10-6; CNTNAP5, p = 1.32×10-6) and one pathway (Neuroactive Ligand Receptor Interactive, p = 1.29×10-5) achieved significance in burden test. In addition, we identified one pair of imaging-genetic components of significant correlation (r = 0.38, p = 9.92×10-6). The imaging component reflected decreased GMV in cases and correlated with intelligence quotient (IQ). IQ mediated the effects of GMV on MDD. The genetic component enriched in two gene sets, namely Singling by G-protein coupled receptors [false discovery rate (FDR) q = 3.23×10-4) and Alzheimer Disease Up (FDR q = 6.12×10-4).

Conclusions: Both rare variants analysis and imaging-genetic analysis found evidence corresponding with the neuroinflammation and synaptic plasticity hypotheses of MDD. The mediation of IQ indicates that genetic component may act on MDD through GMV alteration and cognitive impairment.

Keywords: MRI; Major depressive disorder; parallel ICA; whole exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Asian Continental Ancestry Group
  • Case-Control Studies
  • Cell Adhesion Molecules, Neuronal / genetics*
  • China
  • Depressive Disorder, Major / diagnostic imaging
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / pathology*
  • Female
  • Gray Matter / diagnostic imaging
  • Gray Matter / pathology*
  • Humans
  • Logistic Models
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins / genetics*
  • Organ Size
  • Polymorphism, Single Nucleotide
  • Tumor Suppressor Proteins / genetics*
  • Whole Exome Sequencing*
  • Young Adult

Substances

  • CNTNAP5 protein, human
  • CSMD1 protein, human
  • Cell Adhesion Molecules, Neuronal
  • Membrane Proteins
  • Tumor Suppressor Proteins