Association Between Altered White Matter Integrity And Tryptophan Hydroxylase-2(TPH2) Polymorphism In First-episode Medication-naive Adult Major Depressive Disorder Patients

Objectives:Considerable evidence suggests that the tryptophan hydroxylase-2(TPH2)gene is associated with the pathophysiology of major depressive disorder(MDD).In present study,we aimed to investigate the alterations of white matter integrity in first-episode medication-naive MDD patients,and the impact of TPH2 polymorphism on white matter(WM)integrity in MDD.Methods:One hundred and eighteen first-episode medication-naive patients with MDD and 118 well-matched healthy controls underwent diffusion tensor imaging(DTI)scanning,and genotyped for TPH2 rs4570625 polymorphism.Based on the results of the genotyping of TPH2,patients and controls were subdivided into groups of patients with GG genotype of rs4570625;patients T carrier genotype of rs4570625;healthy controls with GG genotype of rs4570625;healthy controls with GT or TT genotype of rs4570625.Whole brain analyses of fractional anisotropy(FA)were performed using tract-based spatial statistics(TBSS)between MDD and HC and the different genotype subgroups in MDD group or HC group.We chose the whole white matter tracts which shown significantly different FA values(FWE corrected)as the regions-of-interests(ROIs)and extract individual means of FA for ROIs.We performed multivariate analysis of covariance(MANCOVA)with age,sex,education as covariates to compare the FA values of ROIs to confirm the results from TBSS.In addition,for FA values in the anatomical regions,which significantly different between the MDD and control groups,a Pearson partial correlation analysis was performed to investigated their association with the clinical variables(i.e.HDRS scores,illness duration)in the MDD group after adjusting for age,gender,education level.Results:The study showed that patients with MDD had significantly reduced FA values for the genu and body of the corpus callosum(CC)and bilateral anterior corona radiate(ACR).In the MDD patient group,the GG homozygote subgroup exhibited widespread reduction of FA including genu and body of CC,bilateral ACR and bilateral superior corona radiate(SCR)(uncorrected)and significant reduced FA in left retrolenticular portion of the internal capsule and left superior longitudinal fasciculus(SLF)compared with the T carrier(GT/TT)(FWE corrected).No significant differences in FA values were observed between different genotypes among healthy controls.There was no significant correlation between the FA values in any brain region and patients’ clinical variables(both depression severity and illness duration)Conclusion:1.In patients with first-episode depression(MDD),there is reduction in the integrity of the white matter fiber bundles of emotional regulation loop in the unrestrained condition;2.The GG polymorphism in the TPH2-rs4570625 gene may be associated with the MDD affective loop.The decrease of the FA value in the brain suggests that the polymorphism of TPH2-rs457625 may be involved in the pathological mechanism of the destruction of white matter microstructure in patients.