Study On Brain-derived Neurotrophic Factor, Serotonin-transporter-linked Polymorphic Region And Endophenotype Of First-episode Major Depressive Disorder

BackgroundDepressive disorder comprises a series of symptoms and function impairment, with obvious heterogeneity. Through rearch on endophenotype of depression, the group with or without some phenotype can be screeninged to increase the homogeneity of sample, in order to investigate key gene of the phenotype. The endophenotypes selected in our study are depressive emotion and cognitive impairment.Now researches indicate that brain-derived neurotrophic factor (BDNF) gene Val66Met is possible predisposing gene of depression, and hippocampus neurons with Met transfection make BDNF ineffective transport to secretory vesicles, which decreases activity-dependent BDNF secretion and impair cognitive function such as executive function and memory. Serotonin-transporter-linked polymorphic region (5-HTTLPR) also may be predisposing gene of depression. 5-HTTLPR controls transcription activity of serotonin transporter (5-HTT), influencing the concentration of serotonin (5-HT) in synaptic cleft and cognitive function. Meanwhile, BDNF and 5-HT are generally involved in various mechanisms of depression, and plays an important role in neurotrophic factor hypothesis and monoamine hypothesis respectively. It is confirmed that BDNF is the molecule plasticity marking of 5-HT neuron in central nervous system, interacting with 5-HT in intracellular and intercellular levels. So what influence BDNF gene polymorphism and 5-HTTLPR make on endophenotype of depression respectively and their interaction? This is a worthwhile approach, and it has not been reported about this area up to now.ObjectiveTo investigate differences of BDNF gene polymorphism and 5-HTTLPR respectively between patients with first-episode major depressive disorder and healthy volunteers; to investigate influencing factors and correlation respectively between BDNF gene polymorphism, 5-HTTLPR and endophenotype of depression; to investigate interaction of BDNF gene polymorphism and 5-HTTLPR in endophenotype of depression.Methods100 patients with first-episode major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders-Four (DSM-IV) and 100 healthy volunteers were included in the research as study group and control group respectively. Cognitive function of two groups were both assessed by a series of neuropsychology tests as follow: Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), Modified Wisconsin card sorting (M-WCST), Trail Marking Test (TMT) and Tower of Hanoi (TOH). In study group, depressive emotion was evaluated by core symptom score of 24-item Hamilton Depression Scale (HAMD24), and disease severity was evaluated by HAMD total score. Polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) were used to detect BDNF gene polymorphism and 5-HTTLPR.Results(1) Endophenotype of first-episode depression:①Depressive emotion:There was no statistical difference in HAMD core symptom score between depressive patients with and withour psychotic symptoms (P>0.05). ②Cognitive function:1) M-WCST classification in depressive patients without psychotic symptoms was higher than that in patients with psychotic symptoms, while TMT-B consuming time was lower, both with statistical differences (P<0.05). Other neuropsychology tests achievements had no significant differences between these two groups(P>0.05).2) Controlling gender, age, education degree, disease course and psychotic symptoms factors, WAIS-RC VIQ,PIQ,IQ, M-WCST classification,correct were negatively correlated with HAMD core symptom score; while M-WCST wrong,continues wrong,random wrong, TMT-A consuming time, TMT-B consuming time and TOH plan time were positively correlated with HAMD core symptom score.3) In WAIS-RC comprehension,similarity,block design,object assembly,PIQ,IQ, each subtests of M-WCST,TMT and TOH, achievements of control group were significantly better than those of study group (P<0.05 or P<0.01).(2) The analysis of BDNF gene polymorphism:①Distribution of BDNF genotypes and alleles:1) Met allele frequency in study group was higher than that in control group, but Val allele and Val/Val genotype were lower. All differences were statistically significant (P<0.05).2) Controlling gender factor, depression relative risk of individuals carrying Met allele increased 1 times as much as carrying Val allele (OR=2.082,95%CI:1.116～3.884); disease risk of individuals carrying Val/Val genotype decreased a half risk of other genotypes (OR=0.480,95%CI:0.257～0.896). All differences had statistical significance (P<0.05).②The comparison of endophenotype of depression among BDNF genotypes in study group:1) HAMD core symptom score had statistical difference among 3 groups of BDNF genotypes (P<0.01); the score in Val/Val and Val/Met genotypes were both significantly lower than Met/Met genotype respectively (P<0.01). Controlling age, gender,disease course and psychotic symptoms factors, HAMD core symptom score was positively correlated with Met/Met genotype, and was negatively correlated with Val/Val and Val/Met genotypes.2) Except TMT interference, the achievements of all neuropsychology tests had statistical differences among BDNF genotypes (P<0.05 or P<0.01). Moreover, the achievements of those tests were all significantly better in Val/Val genotype than in Met/Met genotype (P≤0.01).(3) The analysis of 5-HTTLPR:①Distribution of 5-HTTLPR genotypes and alleles:The frequency of L/L genotype and L allele in study group was lower than that in control group respectively, and the frequency of S/S genotype and S allele in study group was higher. But all differences were no statistically significant (P>0.05).②The comparison of endophenotype of depression among 5-HTTLPR genotypes in study group:1) HAMD core symptom score had no statistical difference among 3 groups of 5-HTTLPR genotypes (P>0.05). After multiple comparison, the score in L/L genotype was statistically higher than that in S/S genotype (P<0.05). Controlling age,gender,disease course and psychotic symptoms factors, HAMD core symptom score was not statistically correlated with any 5-HTTLPR genotype (P>0.05).2) In WAIS-RC vocabulary,digit symbol,VIQ,PIQ,IQ, subtests of M-WCST except correct, TMT-B consuming time, TOH execution time and total core, the achievements had statistical differences among 5-HTTLPR genotypes (P<0.05 or P<0.01). Moreover, the achievements of WAIS-RC PIQ,all subtests of M-WCST, TMT-A,TMT-B consuming time and TOH total score were significantly better in S/S genotype than in L/L genotype (P<0.05 or P<0.01).(4) gene interaction (BDNF and 5-HTTLPR)①Joint genotype distribution with BDNF and 5-HTTLPR:The frequency of both carrying BDNF Met allele and 5-HTTLPR S allele in study group was higher than that in control group, with statistical difference (P< 0.05).②The influence of different BDNF genotypes and 5-HTTLPR genotypes on disease risk:Controlling gender factor, depression relative risk of individuals carrying both BDNF Met allele and 5-HTTLPR S allele increased 1 times as much as carrying neither BDNF Met allele nor 5-HTTLPR S allele (OR=2.003,95%CI:1.116～3.594); disease risk of individuals carrying BDNF Met allele also was 1 times as much as not carrying this allele (OR=2.082,95%CI:1.116～3.884). All differences were statistically significant (P<0.05).③The influence of different BDNF genotypes and 5-HTTLPR genotypes on endophenotype of depression:1) Main effect of BDNF genotypes on HAMD core symptom score was statistically significant (P<0.01); neither main effect of 5-HTTLPR genotypes nor interaction between BDNF genotypes and 5-HTTLPR genotypes was statistically significant (P>0.05).2) Controlling age,gender,education degree,disease course and psychotic symptoms factors, neither main effect of BDNF genotypes nor that of 5-HTTLPR genotypes on cognitive function was statistically significant (P > 0.05). The interaction between BDNF genotypes and 5-HTTLPR genotypes on WAIS-RC digit span was statistically significant (P<0.05), with no statistical significance on each of other neuropsychology tests (P>0.05).④The influence of different BDNF genotypes and 5-HTTLPR genotypes on disease severity:Controlling gender factor, relative risk of disease severity of patients carrying BDNF Met/Met genotype was about 7 times as high as not carrying this genotype (OR=7.977,95%CI:2.681～23.737), with statistical significance (P<0.05).Conclusion(1) BDNF Val66Met gene polymorphism is statistically different between patients with first-episode major depressive disorder and healthy volunteers, and Met allele is correlated with morbility of depression, regarded as risk factor of disease. Furthermore, its polymorphism is also correlated with endophenotype of depression. The depressive emotion is more serious in patients with Met/Met genotype than Val/Val genotype; meanwhile, the general impairment of cognitive function in Met/Met genotype is also more serious, especially in executive function such as generalization,attention,working memory,cognitive transference,visual discrimination,space perception and plan ability.(2) 5-HTTLPR is not statistically different between patients with first-episode major depressive disorder and healthy volunteers, but the frequency of S/S genotype in depressive patients has higher tendency than that in healthy volunteers. 5-HTTLPR perhaps has no correlation with depressive emotion endophenotype, however it has correlation with cognitive disfunction endophenotype. The general impairment of cognitive function in L/L genotype is more serious, especially in executive function such as comprehension and performance ability,cognitive transference,attention,working memory and completing plan ability.(3) The joint genotype distribution with BDNF Val66Met and 5-HTTLPR is statistically different between patients with first-episode major depressive disorder and healthy volunteers. Depression relative risk of individuals carrying both BDNF Met allele and 5-HTTLPR S allele is significantly higher, and BDNF Met allele plays main effect.(4) Among the influences of BDNF Val66Met gene polymorphism and 5-HTTLPR on endophenotype of depression, BDNF Met/Met genotype generates main effect, and the interaction between BDNF Val66Met gene polymorphism and 5-HTTLPR is significant on attention and short-term memory.