Serotonin System Genes Affecting Depression Frontal Sub-region Structure, Function To Change The Image Genome Research,

Background: Frontal lobe is an important brain region with the function of regulating emotion. Previous studies suggested that patients with depressive disorder had decreased frontal density, volume decreases, and abnormal activation to emotional stimuli. But we had few knowledge about whether such changes has genetic specificity. Frontal lobe is rich in 5-HT neurotransmitters, receptors, and is in close relationship with 5-HT system. So, it has an important basic role to know the genetic specificity of the whole brain in preliminary when analyzing the correlation among subregions of depressed frontal lobe and 5-HT related genes engaged in the four parts of 5-HT system.Objectives: We selected four polymorphic sites comprised in the four parts, including synthesis, translation, receptor and decomposition, in 5-HT related genes—TPH1 (A218C), 5-HTTLPR, 5-HTR2A (T102C), MAOA-u VNTR using the method of genetic imaging, and with the imaging changes of frontal lobe as endophenotypes, to explore the genetic function of 5-HT on abnormal frontal lobe of depressed patients.Methods: 60 patients with major depression and 50 healthy controls which were equal in sex, age, years of education and had negative family history of mental illness were recruited in our study. We detected their brain structure and activation to different emotional stimuli with the task of three-dimension (3D) Structure Magnetic Resonance Imaging and functional Magnetic Resonance Imaging (fMRI). All image date were pretreated by the software of SPM2 and SPM5. Then frontal lobe was extracted as region of interest by WFU software into six subregions—bilateral superior frontal lobe, middle frontal lobe and inferior frontal lobe. Wisconsin card sorting test (WCST) was also performed to examine the function of frontal lobe. All cases were divided into three different genotype using restriction fragment length polymorphism. SPSS11.5 was used to analyze the influence of different genotypes on gray matter concentration (GMC), activation to various emotional stimuli and neurocognitive function, as well as the interactions among the loci.Results:1. Analysis of genetic equilibriumTest of Hardy-Weinberg genetic equilibrium showed that different genotype frequencies in diagnostic groups were in good consistence with the theoretical value,achieveing genetic equilibrium (P>0.05).2. Comparision of states of frontal and psychological testWe found significant differences of GMC in right frontal lobe (superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus) and strength of activation in bilateral superior frontal gyrus, right middle frontal gyrus, bilateral inferior frontal to tasks between diagnostic groups. The two groups also had different scores of Cc, Re, Rf, Rpe scores in WCST (P<0.05).3. Preliminary analysis of genotypes on WCST and frontal lobeModel of COX univariate analysis showed that TPH1 A218C influenced the activation of right middle frontal gyrus, left inferior grontal gyrus, right inferior frontal gyrus in depressed and bilateral inferior frontal lobe in controls significantly (P<0.05); HTR2A T102C influenced the activation of right middle frontal gyrus, right inferior frontal gyrus in depressed and controls significantly (P<0.05); MAOA-uVNTR influenced right superior frontal gyrus, right middle frontal gyrus in depressed and right superior frontal gyrus significantly (P<0.05). These were little effect of polymorphisms on brain structure. TPH1 gene also impacted the scores of Cc, Rf, Rpe in depressed significantly (P<0.05). There was no effect of 5-HTTLPR on psychological results and imaging dates.4. Influence of TPH1 A218C on WCST in depressed groupPatients with different genotypes of TPH1 A218C polymorphism had significant differences in Cc, Rf, Rpe scores (P<0.05). In comparision with patients with CC genotype, patients with AA genotype had significantly reduced scores of Cc, Rf, Rpe, patients with AC genotype also showed reduced score of Rpe (P<0.05).5 Influence of diagnosis and genotype on frontal5.1 GMC of frontal lobeAfter LSD comparison, results only showed that patients the TPH1 AA genotype had reduced GMC in right inferior gyrus when compared to patients with CC genotype; Patients with HTR2A CC genotype had reduced GMC in right middle frontal gyrus when compared to patients with TT genotype and controls with TT or TC genotype (P<0.05). No such significant differences were showed between other groups.5.2 Function of frontal lobeAnalysis with the genotyping factor of TPH1 A218C: In recognition of happy facial expression, activation of right middle frontal gyrus in patients with AA genotype was less than other five groups. Activation in patients and controls with AA or AC genotype were all less than controls with CC genotypes, especially patients with AA genotype. In recognition of sad facial expression, patients and controls with AA genotype showed increased activation in left inferior frontal lobe than patients and controls with AC or CC genotype. Patients with AA genotype showed increased activation in right inferior frontal gyurs than other five groups as well (P<0.05). Analysis with the genotyping factor of HTR2A T102C: In recognition of happy facial expression, activation of right middle frontal gyrus in patients with CC genotype was less than patients and controls with AA of AC genotype. In recognition of sad facial expression, patients with CC genotype showed increase activation in left superior frongal gyrus than controls with TT genotype, increased activation in right middle frontal gyrus than patients with TT of TC genotype and controls with TT genotype and increase activation in right inferior frontal gyrus than patients and controls with TT of TC genotype (P<0.05).Analysis with the genotyping factor of MAOA-uVNTR: In recognition of happy facial expression, activation of right superior reduced significantly in patients with high-activity (H) genotype than patients and controls with low-activity (L) genotype. In recognition of bad facial expression, patients with H genotype showed increased activation in right middle frontal gyrus, left inferior frontal gyrus than patients and controls with L genotype (P<0.05).Interaction of polymorphisms on activation of frontal lobe to emotional recognization: Multivariate analysis of variance showed that superimposition of TPH1 A218C and MAOA-uVNTR existed in abnormal function of left inferior frontal gyrus when recognizing negative emotional stimuli (P<0.05). At the same time, superimposition of TPH1 A218C and HTR2A T102C was found in abnormal function of right middle frontal gyrus when recognizing positive emotional stimuli and right inferior grontal gyrus when recognizing negative emotional stimuli (P<0.05).There was no such effect of superimposition in controls with different genotypes.Conclusion: 5-HT system-related gene polymorphisms impact on cognitive dysfunction of subregions in frontal lobe more than on frontal structure in major depressive disorder apparently. TPH1 and MAOA genes engage in the pathological mechanism attribute to the abnormal activation in emotion recognition of frontal lobe subregions, from the perspective of 5-HT synthesis and decomposition. C allele of HTR2A gene has an effect on the abnormality of frontal lobe, with a possible role of compensation and other factors. No correlation of 5-HTTLPR and the structure, function of frontal lobe is found, the internal mechanism of which still need for more intensive study. There are synergies exist between THP1 and MAOA, TPH1 and HTR2A genes, which confirm the theory that different genes in serotonin system can affect brain function through a common 5-HT feature to some extent. This suggests that there is a genetic basis of 5-HT in depressive frontal lobe, and it is an important ground work for exploring the genetic basis of other major brain regions involved in depression one by one until the whole brain structure and function.