No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study.

BACKGROUND: Two previous studies reported a significant association between a missense polymorphism (Val66Met) in the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder; however, contradictory negative results have also been reported, necessitating further investigation. METHODS: We organized a multicenter study of a relatively large sample of 519 patients with bipolar disorder (according to DSM-IV criteria) and 588 control subjects matched for gender, age, and ethnicity (Japanese). Genotyping was done by polymerase chain reaction-based restriction fragment length polymorphism or direct sequencing. RESULTS: The genotype distributions and allele frequencies were similar among the patients and control subjects. Even if the possible relationships of the polymorphism with several clinical variables (i.e., bipolar I or II, presence of psychotic features, family history, and age of onset) were examined, no variable was related to the polymorphism. CONCLUSIONS: The Val66Met polymorphism of the BDNF gene is unrelated to the development or clinical features of bipolar disorder, at least in a Japanese population.     

Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress.

BACKGROUND: Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. METHODS: We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS: Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). CONCLUSIONS: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.     

Extreme attributions predict transition from depression to mania or hypomania in bipolar disorder

Background

Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that “extreme” (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation.

Method

Outpatients with DSM-IV bipolar I or II disorder (N = 105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat.

Results

Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05).

Conclusions

Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility.     

Genetic dissection of glucocorticoid receptor function in the mouse brain

In the brain, glucocorticoids exert functions in neurogenesis, synaptic plasticity and behavioural responses, as well as in the control of hypothalamic-pituitary-adrenal axis activity. The generation of mice harbouring germline mutations that result either in loss or in gain of glucocorticoid receptor function provided a useful tool for understanding the role of glucocorticoids in the brain in vivo . The improvement of genomic technologies additionally allowed the establishment of mouse models with function-selective point mutations of the receptor as well as the generation of mice harbouring spatially and/or temporally restricted loss of glucocorticoid receptor, specifically within the brain. These models will provide the opportunity to better understand the mechanisms involved in glucocorticoid signalling within the nervous system.     

Association of intronic polymorphism rs3773364 A>G in synapsin‐2 gene with idiopathic epilepsy

In epilepsy, there is a tendency towards recurrent unprovoked seizures. Seizures result due to the excessive electrical misfiring in the brain between neurons and disturbance in neurotransmitter release. Several gene products affect the behavior of these neurons by regulating neurotransmission via several mechanisms. One such gene, Synapsin‐2 (SYN2), involved in synaptogenesis is also reported to regulate the neurotransmitter release. We hypothesized that SYN2 gene and its polymorphisms could affect the process of epileptogenesis and therapeutic response in humans. In this hospital‐based study, we enrolled 372 patients with epilepsy and 199 control subjects. We selected rs3773364 A>G polymorphism in SYN2 gene and analyzed its distribution in north Indian patients with epilepsy and control subjects. Genotyping was carried out by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. According to the results obtained, SYN2 “AG” genotype frequency was significantly higher in patients with epilepsy versus control subjects in north Indian population (P = 0.02, OR = 1.55, 95% CI = 1.06–2.26). After subclassification, we observed higher frequency of AG genotype in idiopathic patients as compared to control subjects (P = 0.01, OR = 1.67, 95% CI = 1.08–2.56). There were no significant differences in genotypic (AG: OR = 0.80, P = 0.377; GG: P = 0.628, OR = 1.17) or allelic (P = 0.86, OR = 1.03) frequency distributions in patients with multiple drug resistance versus patients with drug‐responsive epilepsy. Results from our study indicate the involvement of SYN2 gene polymorphism in conferring risk to epilepsy; however, the genetic variant does not seem to modulate drug‐response in epilepsy pharmacotherapy. Synapse 64:403–408, 2010. © 2009 Wiley‐Liss, Inc.     

-94 G/A polymorphism in the dopamine D1 receptor gene is associated with schizophrenia in a Chinese Han population from Shandong province

The correlation between -94 G/A polymorphism in the dopamine D1 receptor gene and schizophrenia remains poorly understood despite extensive research. This study sought to evaluate the genotypes and allele frequencies of the -94 G/A polymorphism in the dopamine D1 receptor gene by real-time PCR using TaqMan fluorescent probes. One hundred and sixty-two patients with schizophrenia and 101 healthy controls living in Shandong province of China were evaluated. Experimental results showed that the G/A genotype distribution was significantly higher in the schizophrenia patients than in healthy controls. The frequencies of G allele and A allele were not significantly different between the schizophrenia patients and the controls. Thus, the -94 G/A polymorphism in the dopamine D1 receptor gene was found to be associated with schizophrenia in a Chinese Han population from Shandong province.     

中国人群WRN基因多态性与脑膜瘤的关联研究

目的探讨Werner(WRN)基因与中国人群脑膜瘤发病风险的关联。方法对215例病理确诊的脑膜瘤病人和219例健康人,采用Snapshot方法对4个多态性位点(rs3024239、rs2725364、rs1800392、rs1801195)进行基因分型,比较脑膜瘤与健康人群之间WRN基因不同位点基因频率分布差异,并根据性别、年龄及病理亚型进行分层分析。结果 rs3024239多态性位点与内皮型脑膜瘤发病关联,rs3024239位点携带等位基因C的人群内皮型脑膜瘤的发病风险较低(P=0.015)。余3个位点多态性与脑膜瘤无明显相关性(均P>0.05);4个位点基因多态性与不同年龄与性别的脑膜瘤人群的发病风险无明显相关(均P>0.05)。结论中国人群中WRN基因多态性可能与脑膜瘤的发病风险具有相关性,rs3024239位点等位基因C能降低内皮型脑膜瘤的发病风险。     

No association of serotonin transporter gene (SLC6A4) with schizophrenia and bipolar disorder in Japanese patients: association analysis based on linkage disequilibrium

Summary. Serotonin transporter gene (SLC6A4) is one of the most promising candidate genes for psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP). Two functional polymorphisms, 5HTTLPR and 5HTTVNTR, have been a focus for genetic association analyses; however, no conclusive results have been obtained. We conducted, 1) a mutation search of SLC6A4, 2) LD mapping to select ‘tagging’ markers (10 SNPs and 5HTTVNTR, while 5HTTLPR was treated as an independent marker because of its allelic form), and 3) association analysis of these ‘tagging’ markers and independent markers (5HTTLPR and Asn605Lys) with SCZ and BP in Japanese patients. In this mutation search, a nonsynonymous SNP, Asn605Lys, was detected. No associations of ‘tagging’ markers and independent markers with such conditions were found. These results indicate that SLC6A4 might not play a major role in SCZ and BP in Japanese patients, a finding that agrees with both the common disease-common variant hypothesis and common disease-rare variant hypothesis.     

Treatment‐emergent mania/hypomania during antidepressant monotherapy in patients with rapid cycling bipolar disorder

Objective: To study treatment‐emergent mania/hypomania (TEM) associated with second‐generation antidepressant monotherapy in patients with rapid cycling bipolar disorder (RCBD). Methods: Data of patients with RCBD (n = 180) enrolled into two clinical trials were used to study the risk for TEM during second‐generation antidepressant monotherapy. History of TEM was retrospectively determined at the initial assessment by asking patients whether they were exposed to second‐generation antidepressants and if a hypomania/mania episode emerged during the first four weeks of treatment. Data were analyzed using t‐test, chi‐square, and logistic regression. Results: Of the 180 patients (bipolar I disorder, n = 128; bipolar II disorder, n = 52) with RCBD, 85% (n = 153) had at least one antidepressant treatment. Among these patients, 94.1% (144/153) had at least one antidepressant monotherapy treatment. Overall, 49.3% of patients had at least one TEM and 29.1% (116/399) of treatment trials were associated with TEM. In regression analysis, an inverse association between the number of mood episodes in the last 12 months and TEM was observed with an odds ratio of 0.9. However, gender, bipolar subtype, a lifetime history of comorbid anxiety disorder, substance use disorder, or psychosis, and age of mood disorder onset were not associated with TEM. For individual antidepressants, the rates of TEM varied from 42.1% for fluoxetine to 0% for fluvoxamine and mirtazapine. As a group, there was no difference between selective serotonin reuptake inhibitors and venlafaxine or bupropion in the incidence of TEM. Conclusions: Use of second‐generation antidepressants as monotherapy in RCBD is accompanied by clinically relevant rates of TEM. Even in patients with RCBD, differential vulnerabilities to antidepressant TEM may exist.     

Catechol-O-methyltransferase gene Val108/158Met polymorphism in bipolar disorder

Backgrounds

Although several studies have tested the association between bipolar disorder (BD) and the Val108 (H, high-activity allele)/158Met (L, low-activity allele) polymorphism of the catechol-O-methyltransferase (COMT) gene, most of the results showed no significant association. However, an association between the H or L allele and bipolar disorder (BD), particularly, between L allele and rapid-cycling form has been reported; it has also been suggested that the variation in the COMT gene modifies the course of BD and there is a tendency for the L allele amongst the female patients. In this study, the researchers aimed to evaluate the association between BD and COMT gene H/L polymorphism considering the influence of gender in a group of Turkish patients.

Method

One hundred and thirty-five BD patients (71 male and 64 female) and 171 controls were included. Polymerase chain reaction-based endonuclease digestion method was used.

Results

Genotypic distribution in patients and controls were in Hardy-Weinberg equilibrium. No significant difference was found in genotypic and allelic frequencies between patients and controls. However, female patients had H allele more frequently than male patients and female healthy controls. Females had more depressive and less manic episodes than males. Number of total episodes was associated with H allele in all patients.

Conclusion

Distribution of COMT genetic polymorphism was not significantly different between the patients and controls. However, it has been found an association of H allele with female patients and number of episodes among all patients.     

Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder

Panic disorder is a common anxiety disorder characterized by sudden and recurrent panic attacks. Previous studies have indicated significant genetic contributions and a susceptibility locus for panic disorder has been mapped to human chromosome 7p 15. The receptor for Neuropeptide S (NPS) is located in the same genomic region while NPS is known to produce arousal and anxiolytic-like effects in rodents. Here we report that a coding polymorphism in the Neuropeptide S receptor (NPSR) is associated with panic disorder in male patients of Japanese ancestry. The polymorphism (Asn(107)Ile) results in a gain-of-function of the receptor protein by increasing the agonist sensitivity about tenfold. The allele representing the less active isoform (NPSR Asn(107)) was found under-represented in male panic disorder patients, indicating a potential protective function of the protein. Two unrelated groups of patients diagnosed with schizophrenia or attention-deficit/hyperactivity disorder (ADHD) showed no association of particular NPSR alleles with the disorders. These results provide evidence for a gender-specific effect of NPSR in the pathogenesis of panic disorder.     

多巴胺D4受体基因与强迫症的关联

目的：探讨多巴胺D4受体DRD4基因多态性同强迫症（OCD）的关系。方法：采用PCR-AmFLP技术测定105例OCD患者和100例健康对照者的DRD4基因48bp可变数目重复序列的多态性。结果：OCD组与对照组间等位基因频数分布差异显著（P〈0.05）;其中患者组在4倍48bp重复序列纯合子的分布上明显低于对照组（P〈0.05）。结论：DRD4基因48bp可变数目重复序列的多态性可能与强迫症的发病有关。     

色氨酸羟化酶基因多态性对抑郁症患者额叶亚区改变影响的影像学研究

目的 探讨色氨酸羟化酶(TPH1)基因A218C多态性对抑郁症患者额叶亚区结构、功能的影响.方法 对60例抑郁症患者(患者组)及52名性别、年龄、受教育年限匹配的健康人(对照组)进行磁共振扫描、TPH1基因分型,比较不同诊断组、基因型组内额叶密度、激活强度的差异.结果(1)AA基因型患者组右额下回灰质密度值(1.25±0.03;n=6)较CC基因型对照组(1.37±0.10;n=13)显著降低,差异有统计学意义(F=2.01,P=0.19;经LSD比较,P=0.04).(2)负性面部表情识别时,AA基因型患者组左额下回(0.19±0.31; n=5)激活强度值较AC基因型患者组(-0.03±0.34;n=13)、CC基因型患者组(-0.11±0.46;n=8)、AC基因型对照组(-0.03±0.23; n=18)、CC基因型对照组(-0.07±0.26;n=10)均显著增强,差异均有统计学意义(F=4.47,P=0.00;经SD比较,P分别=0.02,0.03,0.02,0.00);AA基因型对照组左额下回(0.15±0.15,n=6)激活强度值较AC基因型对照组、CC基因型对照组均显著增强,差异均有统计学意义(F=4.47,P=0.00;经LSD比较,P分别=0.02,0.02).同时,AA基因型患者组右额下回(0.33±0.27)激活强度值较其余5组(0.10±0.43; -0.04±0.25;0.05±0.16;0.02±0.28;-0.12±0.31)均显著增强,差异均有统计学意义(F=4.23,P=0.03;经LSD比较;P分别=0.04,0.02,0.04,0.03,0.02).结论 TPH1 A等位基因对抑郁症患者额叶亚区功能有一定程度的损害作用,可能构成抑郁症额叶异常的部分遗传学基础.     

Frequencies of single nucleotide polymorphism in alcohol dehydrogenase7 gene in patients with multiple system atrophy and controls.

A polymerase chain reaction and direct sequencing of the ADH7 gene were carried out in 50 controls and 50 patients with probable multiple system atrophy (MSA). Seven SNPs, one insertion, and one mismatch were found in patients with MSA and controls. There was no significant difference in the frequencies of each SNP between the patients and the controls (P > 0.05). Interpretation of this negative finding should be cautious in view of the relatively small number of cases.     

The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder.

BACKGROUND: Although the pathogenesis of bipolar disorder remains unclear, heritable factors have been shown to be involved. The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which is known to play important roles in neurite growth and axonal guidance. METHODS: We examined patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) in Japanese ethnicity for genetic association using eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR. RESULTS: Significant allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was a significant association with major depression in six SNPs. S796 allele carriers were in excess in bipolar II patients (p = .0046, odds ratio = 3.1, 95% CI 1.53-8.76). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). CONCLUSIONS: Our results suggest that genetic variations in the BCR gene could confer susceptibility to bipolar disorder and major depressive disorder.