The cumulative effect of genetic polymorphisms on depression and brain structural integrity

Hum Brain Mapp. 2016 Jun;37(6):2173-84. doi: 10.1002/hbm.23165. Epub 2016 Mar 9.


In major depressive disorder (MDD), the need to study multiple-gene effect on brain structure is emerging. Our aim was to assess the effect of accumulation of specific SERT, BDNF and COMT gene functional polymorphisms on brain structure in MDD patients. Seventy-seven MDD patients and 66 controls underwent a clinical assessment, genetic testing and MRI scan. Compared with controls, patients were more BDNF-Val homozygotes, COMT-Met carriers and SERT-L' carriers. Thus, subjects were split into three groups: 1. High-frequency susceptibility polymorphism group (hfSP, subjects with all three SPs); 2. Intermediate-frequency SP group (ifSP, two SPs); and 3. Low-frequency SP group (lfSP, one/none SP). Cortical thickness, volumetry of hippocampus, amygdala and subcortical structures, and white matter (WM) tract integrity were assessed. Compared to controls, hfSP patients showed thinning of the middle frontal cortex bilaterally, left frontal pole, and right lateral occipital cortex, and smaller hippocampal volume bilaterally; and both hfSP and lfSP patient groups showed thinning of the left inferior parietal cortex and reduced WM integrity of the corpus callosum. Compared to patients, hfSP controls showed greater integrity of the fronto-occipital cortices and corpus callosum. We showed that cortical prefrontal and occipital damage of MDD patients is modulated by the SP accumulation, while damage to the parietal cortex and corpus callosum seem to be independent of genetic accumulation. HfSP controls may experience protective mechanisms leading to a preserved integrity of critical cortical and WM regions. Investigating the effect of multiple genes is promising to understand the pathological mechanisms underlying MDD. Hum Brain Mapp 37:2173-2184, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: accumulation model; cortical thickness; functional polymorphisms; major depression disorder; tractography.

MeSH terms

  • Adult
  • Brain / diagnostic imaging*
  • Brain-Derived Neurotrophic Factor / genetics*
  • Catechol O-Methyltransferase / genetics*
  • Depressive Disorder, Major / diagnostic imaging*
  • Depressive Disorder, Major / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Gray Matter / diagnostic imaging
  • Humans
  • Interview, Psychological
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Organ Size
  • Polymorphism, Single Nucleotide
  • Psychiatric Status Rating Scales
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • White Matter / diagnostic imaging
  • Young Adult


  • Brain-Derived Neurotrophic Factor
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • BDNF protein, human
  • COMT protein, human
  • Catechol O-Methyltransferase