Three-way interaction of 5-HTTLPR, BDNF Vall66Met and COMT Val158Met polymorphisms and its effect on regional gray matter volume in patients with Major Depressive Disorder (P2.156)

Objective. The aim of this study was to assess whether there is a complex three-way interaction between SERT, BDNF and COMT genes functional polymorphisms in patients with major depressive disorder (MDD) and whether it affects their cerebral structural integrity. Background. Up to date, several genetic polymorphisms have been associated with susceptibility for MDD, but usually with inconsistent results. Methods. Seventy-eight MDD patients and 66 healthy controls (HC) underwent genetic testing for 5-HTTLPR, BDNF Val66Met and COMT Val158Met polymorphisms, T1-weighted MRI scan, and a comprehensive clinical assessment. Compared with controls, patients were more BDNF-Val homozygotes (MDD=53; HC=32; p=0.013), COMT Met carriers (MDD=63; HC=47; trend of significance, p=0.058) and SERT L’ carriers (MDD=65; HC=47; trend of significance, p=0.056) . Based on these results, all patients and controls were separated into three groups: 1. High risk group, i.e., patients or controls with all three susceptibility polymorphisms (SP); 2. Intermediate risk group (two SPs); and 3. Low risk group (one or none SPs). Voxel-Based Morphometry (VBM) in SPM8 was performed to assess differences in regional gray matter (GM) volumes between patients and controls taking into account their genetic background. Results: The High risk group was significantly larger among the patients than the controls (MDD= 40; HC= 17; p=0.001). Compared to the Low risk control group, the High risk patient group showed reduced GM volume in the right middle and inferior orbitofrontal cortex bilaterally, and left superior frontal, inferior temporal and lingual gyri. Conclusions: The accumulation of SPs in MDD patients and HC is associated with volume alterations of specific brain regions known to be vulnerable in MDD that are not visible when comparing each SP separately. Our findings suggest that observing differences among patients based on the accumulation or interaction of genetic risk factors is necessary to obtain greater understanding of MDD pathological mechanisms.