Chih-Ya Cheng

Association study of a brain‐derived neurotrophic‐factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response

Preclinical studies have shown that brain‐derived neurotrophic factor (BDNF) may be involved in both antidepressant action and the pathophysiology of major depressive disorder (MDD). The present study tested the hypothesis that the BDNF‐gene Val66Met polymorphism is associated with MDD, its clinical manifestations, and antidepressant response. To elucidate a genetic predisposition of MDD, we studied BDNF‐gene Val66Met polymorphism in 152 MDD patients in 255 normal controls. We also examined the association of this polymorphism and fluoxetine therapeutic response in 110 MDD patients who received a 4‐week fluoxetine treatment. No significant differences were demonstrated for the genotype or allele frequency of the BDNF polymorphism comparing the MDD and control groups. Further, no significant differences were noted comparing the three‐genotype groups for depressive‐cluster symptoms. However, a trend (P = 0.086) to improved 4‐week‐fluoxetine antidepressant response was demonstrated for heterozygous patients in comparison to homozygous analogs. This finding suggests the BDNF polymorphism investigated plays no major role in the pathogenesis of MDD.

Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia.

It is known that a syndrome resembling schizophrenia is produced by the N-methyl-d-aspartate receptor antagonists. It has also been demonstrated that the level of an ionotropic N-methyl-d-aspartate 2B subunit (GRIN2B) of the glutamate receptor tends to increase after subchronic administration of clozapine, suggesting that GRIN2B may play an active role in the pathogenesis of schizophrenia and the function of clozapine medication. We studied 100 schizophrenic patients, investigating the associations for the GRIN2B genetic variants, and psychiatric symptoms and clozapine response. No significant differences were demonstrated comparing these three groups in terms of the baseline Brief Psychiatric Rating Scale (BPRS) score (P = 0.441). The percentage of patients scoring within 20% of baseline BPRS after clozapine treatment was similar for the three genotype groups (P = 0.132). A marginally higher mean clozapine dosage was revealed, however, for patients bearing the 2664C/C genotype (P = 0.013). Although replication of this research is required to confirm the results, an association for the GRIN2B C2664T polymorphism and clozapine treatment is suggested from our findings, which may assist in the prediction of optimal dosage for schizophrenic patients.

Association Study of the 5-HT6 Receptor Polymorphism (C267T) and Symptomatology and Antidepressant Response in Major Depressive Disorders

The serotonergic neurotransmitter system has been implicated in the pathogenesis of major depressive disorder (MDD). Of the 14 human serotonin (5-HT) receptors, the 5-HT6 receptor may be a candidate for the study of MDD because of its relative abundance in certain limbic areas and its high affinity to several antidepressants. The present study tested the hypothesis that a 5-HT6 genetic polymorphism (C267T) is associated with the clinical manifestations of, and/or antidepressant response in, MDD. The Hamilton Depression Rating Scale was used to assess 57 MDD patients before antidepressant treatment, with 34 patients completing the 4-week treatment and evaluation. The results of the association study provide that the 5-HT6 C267T genetic variant does not play a major role in producing the clinical manifestations or antidepressant response for MDD patients. Further study with a functional 5-HT6 polymorphism is needed to explore the role of 5-HT6 in the pathogenesis of MDD.

Study of the Association between Alzheimer’s Disease and Angiotensin-Converting Enzyme Gene Polymorphism Using DNA from Lymphocytes

Angiotensin-converting enzyme (ACE) may play a role in cognition and memory. A recent study found that a 287-bp insertion/deletion (I/D) polymorphism of the ACE gene is associated with susceptibility to Alzheimer’s disease (AD). However, this finding has not been replicated by all studies. These discrepancies may be due to the difference in ethnic background. Therefore, we investigated the possibility of such an association in 173 AD patients and 286 normal controls from a Chinese population. We found that there is an increased frequency of the ACE I allele in AD patients and the odds ratio for bearers of the I allele was 2.88. Our findings further support previous reports of an association between ACE polymorphism and AD. The implication of the ACE I/D polymorphism in the pathogenesis of AD warrants further exploration.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in Parkinson's disease and age of onset

Given the implications with respect to neuronal survival and the decreased level of the protein in the striatal region in Parkinsons disease (PD), brain-derived neurotrophic factor (BDNF) may be a candidate gene conferring susceptibility to PD. In a recent study of a Japanese population, a functional BDNF Val66Met polymorphism was associated with PD, however, an analogous investigation of a western population did not replicate this finding. In the present study of a Chinese sample, we have investigated the associations between the BDNF polymorphism and susceptibility to PD and PD onset age. The distribution of the BDNF genotypes and alleles did not differ significantly comparing PD patients and controls. Further, the onset age was not significantly different comparing the three BDNF genotype groups. Thus, our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of PD in the Chinese population. Other BDNF genetic variants, and the association of these variants with PD symptomatology or treatment response, may merit further investigation.

A study of the association of (Val66Met) polymorphism in the brain-derived neurotrophic factor gene with alcohol dependence and extreme violence in Chinese males.

From studies of genetic-knockout animals, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth-factor family, has been implicated in both alcohol preference and aggressive behaviour. To test whether a BDNF genetic variant may be associated with alcohol-dependent and violent behaviours, we studied Val66Met polymorphism of the BDNF-gene in 110 cases of alcohol-dependence, in 134 extremely violent convicts, and in 149 individuals without psychosis or mood disorders. We also examined the association of this polymorphism with antisocial personality disorder comorbidity in the extremely violent convicts. The results showed that the genotype and allele frequencies for Val66Met polymorphism at the BDNF-gene site did not differ among the three groups. Furthermore, it was not demonstrated that this polymorphism is associated with antisocial personality disorder comorbidity in the extremely violent convicts. Based on these findings, it seems reasonable to suggest that this BDNF-gene Val66Met polymorphism is unlikely to play a major role in the genetic susceptibility to the traits of alcohol-dependence or violence proneness.

Association Study of a Brain-Derived Neurotrophic Factor (Val66Met) Genetic Polymorphism and Panic Disorder

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, plays an important role in the development, maintenance and function of several neuronal systems. Recent studies have demonstrated that antidepressants, commonly used for panic disorder treatment, can increase central BDNF. In addition, animals with BDNF deficits have higher levels of anxiety when exposed to stressors in comparison to normal controls. The present study tested the hypothesis that the BDNF gene Val66Met polymorphism is associated with panic disorder. In this study, therefore, the incidence of this polymorphism was compared in 103 panic disorder patients and 180 normal controls. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing the two groups. Furthermore, no association was demonstrated between this BDNF polymorphism and either mitral valve prolapse or agoraphobia in panic disorder patients. These findings suggest that the investigated BDNF polymorphism does not play a major role in the pathogenesis of panic disorder in this Chinese population. Further studies exploring the relationship between genetic variations of BDNF and the cerebral atrophy associated with, and antidepressant treatment response in, panic disorder may be appropriate.

Support for the involvement of the KCNK2 gene in major depressive disorder and response to antidepressant treatment.

Objective The aim of this study was to examine the associations between genetic variations in the human KCNK2 gene and major depressive disorder (MDD) and response to antidepressant treatment. Method Four hundred and forty-nine patients with MDD and 421 normal controls were included in the study; among the MDD patients, 158 were further followed-up for 8 weeks to assess their response to antidepressant treatment. Five polymorphisms (rs12131478, rs6667764, rs10494994, rs11583745 and rs6686529) of the KCNK2 gene were investigated in terms of their association with MDD and antidepressant treatment efficacy. Results The genotype frequency of rs6686529 differed significantly between the MDD patients and controls (uncorrected P = 0.00052) and remained statistically significant after correction for multiple comparisons. Individuals with homozygous genotypes (CC or GG) showed greater susceptibility to MDD than those with heterozygous genotypes, indicating a possible heterosis effect of the polymorphism on MDD. In addition, this polymorphism also affected the efficacy of antidepressant treatment: the CC carriers had a greater probability of achieving remission after 8 weeks of treatment than the G-allele carriers [odds ratio = 2.55 (95% confidence interval = 1.11–5.88)]. Conclusion Our findings are in line with those of animal studies, and show that KCNK2 is related to the susceptibility to MDD, and involved in antidepressant treatment response. However, the finding of heterosis association of rs6686529 and MDD may be mechanistic, and further replication studies will be essential.

X-box binding protein 1 (XBP1) C-116G polymorphisms in bipolar disorders and age of onset

X-box binding protein 1 (XBP1), a critical gene in the endoplasmic reticulum stress response, is located on chromosome 22q12, which has been linked with bipolar disorders in several studies. Recently, associations have been reported between a polymorphism (-116C --> G) in the promoter region of XBP1, and bipolar disorders in both case-control study and family-based association study, however, this finding is not yet confirmed by other research using independent sample populations. To replicate this finding and determine the association between onset age of bipolar disorders and the XBP1 C--116G polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (153 bipolar disorder patients and 174 controls). We were unable, however, to demonstrate a significant association between the C--116G polymorphism and bipolar disorders (P = 0.674 for genotype and P = 0.436 for allele frequency) or age at onset (P = 0.563). Further, no association was demonstrated between this polymorphism and family history in bipolar disorder patients. These negative findings suggest that the XBP1 C--116G polymorphism does not play a major role in the pathogenesis of bipolar disorders in Chinese populations.

Association study of the dopamine and serotonin transporter genetic polymorphisms and methamphetamine abuse in Chinese males

Summary. The dopamine transporter (DAT) and the serotonin transporter (5-HTT) play important roles in methamphetamine (METH) dependence because they are the target of METH action. For this study, the association between the DAT and 5-HTT polymorphisms and METH dependence were investigated for a Chinese-male sample population. The investigated polymorphisms included those of the DAT 3′-variable number tandem repeat, the 5-HTT gene promoter and a 5-HTT variable number tandem repeat polymorphisms. No significant difference was demonstrated for genotype or allele frequency, when comparing METH dependent and control cases for the DAT and the 5-HTT polymorphisms. The findings of this study suggest that these polymorphisms do not play major roles in METH dependence in the Chinese-male population.