Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder

Background

Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neurotransmission in the pathogenesis of obsessive–compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-d-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes.

Methods

Between 2003 and 2008, we performed a case–control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions.

Results

We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37–4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22–3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions.

Limitations

Study limitations included the risk of population stratification associated with the case–control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B.

Conclusion

Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.     

A Novel <Emphasis Type="Italic">SYNJ1</Emphasis> Mutation in a Tunisian Family with Juvenile Parkinson’s Disease Associated with Epilepsy

We investigated the effect of a set of SNPs within 5 genes identified by GWASs as possible risk genes for schizophrenia (SCZ) in two independent samples, comprising 176 SCZ patients and 326 controls of Korean origin and 83 SCZ patients and 194 controls of Italian origin. The PANSS was used to assess psychopathology severity and antipsychotic response (AR). Several clinical features were assessed at recruitment. In the Korean sample, the SP4 gene haplotype rs2282888-rs2237304-rs10272006-rs12673091 (p?=?0.02) was associated with SCZ. In the Italian sample, PPP3CC rs11780915 (genotypic: p?=?0.006; allelic: p?=?0.001) and rs2249098 (genotypic: p?=?0.0004; allelic: p?=?0.00006) were associated with SCZ, as well as the PPP3CC rs11780915-rs10108011-rs2249098 and the ZNF804A rs7603001-rs1344706 haplotypes (p?=?0.03 and p?=?0.02). Several RORA variants were associated with AR in both the samples, although only the haplotype rs1020729-rs1871858 in the Korean sample survived to the statistical correction (p?=?0.01). Exploratory analyses suggested that: (1) PPP3CC, ST8SIA2, and SP4 genes may modulate psychotic symptoms, and (2) RORA and ZNF804A genes may influence AR. Our results partially support a role for these genes in SCZ and AR. Analyses in well phenotyped samples may help to refine the role of the genes identified by GWASs.     

High ceruloplasmin levels are associated with obsessive compulsive disorder: a case control study

Background

Frizzled 3 (Fzd3) is a receptor required for the Wnt-signaling pathway, which has been implicated in the development of the central nervous system, including synaptogenesis and structural plasticity. We previously found a significant association between the FZD3 gene and susceptibility to schizophrenia, but subsequent studies showed inconsistent findings. To understand the roles of the FZD3 gene in psychotic disorders further, it should be useful to examine FZD3 in patients with methamphetamine psychosis because the clinical features of methamphetamine psychosis are similar to those of schizophrenia.

Methods

Six SNPs of FZD3, rs3757888 in the 3' flanking region, rs960914 in the intron 3, rs2241802, a synonymous SNP in the exon5, rs2323019 and rs352203 in the intron 5, and rs880481 in the intron 7, were selected based on the previous schizophrenic studies and analyzed in 188 patients with methamphetamine psychosis and 240 age- and gender-matched controls.

Results

A case-control association analyses revealed that two kinds of FZD3 haplotypes showed strong associations with methamphetamine psychosis (p < 0.00001). Having the G-A-T-G or A-G-C-A haplotype of rs2241802-rs2323019-rs352203-rs880481 was a potent negative risk factor (odds ratios were 0.13 and 0.086, respectively) for methamphetamine psychosis.

Conclusion

Our present and previous findings indicate that genetic variants of the FZD3 gene affect susceptibility to two analogous but distinct dopamine-related psychoses, endogenous and substance-induced psychosis.     

Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene

Objectives

The serotonergic system plays an important pathophysiological role in various psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is involved in the differentiation and survival of serotonergic neurons. A previous study showed that low serum BDNF levels were associated with strong loudness dependence of auditory evoked potentials (LDAEP) as a reflection of low central serotonergic activity. To evaluate the genetic basis of this relationship, we studied whether the LDAEP is correlated with genetic variants within the BDNF gene.

Methods

Ninety five healthy subjects (41 males, 54 females) received electrophysiological recording of LDAEP and blood drawing for BDNF genotyping. Three BDNF markers (including the single nucleotide polymorphism rs6265(Val66Met)) were analyzed.

Results

Haplotype analysis revealed stronger LDAEP values in carriers of the G(Val)-C-T [rs6265(Val66Met)-rs2030324-rs1491850] haplotype within the BDNF gene in comparison to other haplotype carriers. These findings were demonstrated for the LDAEP of both left and right primary auditory cortices as well as for the vertex electrode (Cz).

Conclusion

Subjects with the BDNF haplotype G(Val)-C-T seem to be characterized by low serotonergic activity as well as possibly by low serum BDNF levels. These findings need replication in independent samples.     

Single Nucleotide Polymorphisms in SLC19A1 and SLC25A9 Are Associated with Childhood Autism Spectrum Disorder in the Chinese Han Population

Genetic variants have been implicated in the development of autism spectrum disorder (ASD). Recent studies suggest that solute carriers (SLCs) may play a role in the etiology of ASD. This purpose of this study was to determine the association between single nucleotide polymorphisms (SNPs) in SLC19A1 and SLC25A12 genes with childhood ASD in a Chinese Han population. A total of 201 autistic children and 200 age- and gender-matched healthy controls were recruited. A TaqMan probe-based real-time PCR approach was used to determine genotypes of SNPs corresponding to rs1023159 and rs1051266 in SLC19A1, and rs2056202 and rs2292813 in SLC25A12. Our results showed that both the T/T genotype of rs1051266 (odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.06–3.23, P = 0.0301) and the T allele (OR = 1.77, 95% CI = 1.07–2.90, P = 0.0249) of rs2292813 were significantly associated with an increased risk of childhood ASD. In addition, the G-C haplotype of rs1023159-rs1051266 in SCL19A1 (OR = 0.71, 95% CI = 0.51–0.98, P = 0.0389) and C-C haplotype of rs2056202-rs2292813 in SLC25A12 (OR = 0.58, 95% CI = 0.35–0.96, P = 0.0325) were associated with decreased risks of childhood ASD. There was no significant association between genotypes and allele frequencies with the severity of the disease. Our study suggests that these genetic variants of SLC19A1 and SLC25A12 may be associated with risks for childhood ASD.     

Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population

Background

A genome-wide association study (GWAS) identified significant association between variants in MEIS1, BTBD9, and MAP2K5/SKOR1 and restless legs syndrome (RLS). However, many independent replication studies are needed to unequivocally establish a valid genotype-phenotype association across various populations. To further validate the GWAS findings, we investigated three variants, rs2300478 in MEIS1, rs9357271 in BTBD9, and rs1026732 in MAP2K5/SKOR1 in 38 RLS families and 189 RLS patients/560 controls from the US for their association with RLS.

Method

Both family-based and population-based case-control association studies were carried out.

Results

The family-based study showed that SNP rs1026732 in MAP2K5/SKOR1 was significantly associated with RLS (P = 0.01). Case-control association studies showed significant association between all three variants and RLS (P = 0.0001/OR = 1.65, P = 0.0021/OR = 1.59, and P = 0.0011/OR = 1.55 for rs2300478, rs9357271, and rs1026732, respectively).

Conclusion

Variants in MEIS1, BTBD9, and MAP2K5/SKOR1 confer a significant risk of RLS in a US population.     

Association Study of <Emphasis Type="Italic">VMAT1</Emphasis> Polymorphisms and Suicide Behavior

Genetic association studies have linked suicide behavior with genes encoding transporters of monoamine. Variants in the vesicular monoamine transporter 1 (VMAT1) have been previously shown to be associated with several psychiatric disorders including schizophrenia and bipolar disorder. However, their association with suicide behavior has not been explored. In the present study, we genotyped three single-nucleotide polymorphisms (rs2270637, rs1390938, and rs2279709) within this gene in 100 individuals who attempted suicide, 236 suicide victims, and 300 control subjects without any history of psychiatric disorders or suicide ideation. We demonstrated no difference in genotype, allele, or haplotype frequencies of theses single-nucleotide polymorphisms between the study groups. Consequently, contribution of VMAT1 in risk of psychiatric disorders might be independent of suicide behavior. Future studies with larger sample sizes are needed to confirm our results.     

Association between cerebral dopamine neurotrophic factor (<Emphasis Type="Italic">CDNF</Emphasis>) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Background

Schizophrenia (SZ) is a complex polygenic psychiatric disorder caused in part by abnormal dopamine levels. Cerebral dopamine neurotrophic factor (CDNF) 2 is known to protect and repair the dopaminergic system. Dopamine dysfunction is one of the pathogenesis of SZ. However, the relationship between CDNF2 and SZ has not been previously investigated. We speculated that CDNF2 may be a susceptibility factor for SZ.

Methods

To address this issue, we carried out a study to investigate the association between CDNF2 and SZ in the total sample 1371 (670 SZ patients and 701 healthy controls) Han Chinese population. Stage 1 included 528 SZ patients and 528 healthy controls; and stage 2 included 142 SZ patients and 173 healthy controls. The allele and genotype frequencies of five single nucleotide polymorphisms (rs2577074, rs2577075, rs2249810, rs6506891, and rs2118343) of CDNF2 were compared between patients and controls.

Results

We found a significant association in allele and genotype frequencies between the two groups at rs2249810 (χ² = 4.38 and 6.45, respectively; P = 0.03 and 0.04, respectively). An association was also observed in males at rs2249810 (χ² = 8.76; P = 0.03). Haplotype TGATC differed between SZ and controls in stage 2 samples (χ² = 6.38; P = 0.01), and rs2118343 genotypes were associated with negative factor scores (F = 4.396; P = 0.01).

Conclusions

These results suggest that rs2249810 and haplotype TGATC of CDNF2 are an SZ susceptibility locus and factor, respectively, and that rs2118343 genotypes are associated with negative symptoms of SZ in the Han Chinese population.

     

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

Background

Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD.

Methods

Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT.

Results

A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5′ region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplotype block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.

Limitations

The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.

Conclusion

The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.     

Lack of association of indoleamine 2,3-dioxygenase polymorphisms with interferon-alpha-related depression in hepatitis C

Background

Major depression is a frequent adverse effect of interferon-alpha (IFN-α) therapy. Although the indoleamine 2,3-dioxygenase (IDO) enzyme seems to be involved in the pathophysiology of IFN-α-induced depression, no pharmacogenetic study has investigated whether variation in the IDO gene modifies vulnerability to this adverse effect.

Methods

A cross-sectional study assessing 277 hepatitis C patients recruited in two specialized outpatient clinics of Brazil. They were interviewed with the Mini International Neuropsychiatric Interview (MINI) approximately 1 month after the end of IFN-α plus ribavirin therapy. Genomic DNA of individuals was extracted from venous blood. Three IDO single-nucleotide polymorphisms (SNPs) were genotyped (rs3824259; rs10089084 and rs35099072).

Results

MINI indicated that 21.3% of the sample met criteria for a major depressive episode during the course of IFN-α therapy. No association with the diagnosis of a major depressive episode during the course of IFN-α therapy was observed genotype or allele-wise (p > 0.05). Current major depression and/or current anxiety disorder was significantly associated with IFN-α-related depression (p < 0.005). However, gender, age, route of infection, result of the antiviral treatment, past history of substance use disorders, depression or any other psychiatric disorder showed no association with IFN-α-related depression (p > 0.05).

Conclusions

Our results suggest no influence of the variants in the IDO gene and the diagnosis of interferon-α-related depression in the Brazilian population. Interferon-α-related depression may impose persistent psychopathology on at least 15% of the depressed patients even 2 years after antiviral therapy termination. The cross-sectional design is a limitation of our study, predisposing memory bias. Prospective pharmacogenetic studies are warranted to continue investigation of the impact of IDO polymorphisms on the development of IFN-α-induced depression.     

Larger than life: overestimation of object size is moderated by personal relevance in obsessive-compulsive disorder

Background and Objectives

Along with other cognitive biases overestimation of threat (OET) has been implicated in the pathogenesis of obsessive–compulsive disorder (OCD). The present study investigated whether OET would not only manifest in cognitive distortions but, also in overestimations of the object size of disorder-related visual objects.

Methods

A total of 65 participants with OCD and 55 healthy controls who were recruited via OCD online forums underwent an incidental learning paradigm consisting of two blocks. In Block 1, participants were asked to rate the valence and the personal relevance for individual OCD concerns of 40 pictures which varied in size. Differences in size, however, were not explicitly communicated to the participants. Stimuli were selected from four categories: 1. neutral, 2. fear-related but OCD-unrelated, 3. washing (OCD-related), and 4. checking (OCD-related). In Block 2, participants were asked to recollect the original size of each stimulus (depicted as a small thumbnail) on a seven point scale.

Results

Whereas few group differences emerged for pre-defined OCD items, OCD-relevant items (individual judgments) were judged as significantly larger by patients with OCD relative to controls. The opposite pattern emerged for neutral items.

Limitations

The sample was recruited via online forums and had probable but not externally validated diagnoses of OCD. No psychiatric control group was recruited.

Conclusions

The present study indicates that OET may extend to neuropsychological tasks. Further research is needed to pinpoint whether OET occurs at the level of encoding suggesting a perceptual bias and/or occurs at the level of retrieval suggesting a memory bias.     

Effect of the Dysbindin Gene on Antimanic Agents in Patients with Bipolar I Disorder

Objective

We previously reported an association between dysbindin gene (DTNBP1) variants and bipolar I disorder (BID). This paper expands upon previous findings suggesting that DTNBP1 variants may play a role in the response to acute mood stabilizer treatment.

Methods

A total of 45 BID patients were treated with antimanic agents (lithium, valproate, or carbamazepine) for an average of 36.52 (±19.87) days. After treatment, the patients were evaluated using the Clinical Global Impression (CGI) scale and the Young Mania Rating Scale (YMRS) and genotyped for their DTNBP1 variants (rs3213207 A/G, rs1011313 C/T, rs2005976 G/A, rs760761 C/T and rs2619522 A/C).

Results

There was no association between the variants investigated and response to mood stabilizer treatment, even after considering possible stratification factors.

Conclusion

Although the small number of subjects is an important limitation in our study, DTNBP1 does not seem to be involved in acute antimanic efficacy.     

Association of the functional serotonin transporter haplotype with familial form of obsessive compulsive disorder in Iranian patients

Objective: Several polymorphisms have been reported in the 5-HTTLPR of the serotonin transporter gene (SLC6A4). Family-based evidences for the association of 5-HTTLPR polymorphisms with OCD were previously reported but results were controversial. The present study investigated the possible correlation of SLC6A4 polymorphisms (5-HTTLPR, rs25532, rs25531) in Iranian OCD patients considering gender, age of onset, family history of psychiatric disorders, obsessive and compulsive subtypes and severities.

Methods: The included OCD patients fulfilled the criteria for DSM-IV-TR whom Y-BOCS score was more than 9. Blood samples (184 cases and 192 controls) were genotyped by means of PCR-RFLP.

Results: Mean of Y-BOCS scores of included patients was 20.1?±?0.69. Rs25532?CC genotype showed significant association with OCD in men and were detected more in the patients reported positive family history of psychiatric disorders but the other single loci (5-HTTLPR and rs25531) did not associate with OCD. Haplotype analysis showed significant association of 14-A variant with OCD and revealed the association of 14-A/14-A genotype with familial form of OCD.

Conclusions: The findings of this study showed the association of SLC6A4 variants with familial form of OCD and proposed stratified analyses in the genetic studies facilitate identification of genetic risk factors for this heterogeneous disorder.     

ESPECTRA: Searching the Bipolar Spectrum in Eating Disorder patients

Background

Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression.

Methods

We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes.

Results

We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification.

Conclusion

Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.     

Neuroinflammation in the fetus exposed to maternal obsessive–compulsive disorder during pregnancy: A comparative study on cord blood tumor necrosis factor-alpha levels

Objective

The relationship between maternal psychiatric disorders and fetal neurodevelopment is unclear. Obsessive–compulsive disorder (OCD) is relatively frequent during pregnancy. The study aimed to investigate whether maternal OCD during pregnancy affects fetal circulating tumor necrosis factor-alpha (TNF-α) levels, an important pro-inflammatory cytokine, by comparing cord blood TNF-α levels in newborn infants of women with and without OCD.

Methods

The study sample included 7 women with OCD and 30 healthy women. OCD and other psychiatric diagnoses were screened by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The blood sample for the determination of TNF-α level was obtained from the umbilical cord during delivery.

Results

Cord blood TNF-α levels in newborn infants exposed to maternal OCD were significantly higher compared to non-exposed infants. Maternal anxiety symptom level was found to positively correlate with cord blood TNF-α levels in newborn infants of women with OCD.

Conclusion

The study results imply that maternal OCD during pregnancy may lead to neuroinflammation in the developing fetal brain through higher levels of circulating TNF-α.     

No Effect of Serotoninergic Gene Variants on Response to Interpersonal Counseling and Antidepressants in Major Depression

Objective

Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated.

Methods

One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417).

Results

IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome.

Conclusion

Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.     

Association analysis of ANK3 variants with bipolar disorder in the Korean population

Background: Bipolar disorder (BD) is a major psychiatric disorder characterized by alternating mood episodes, including major depressive, hypomanic, and manic episodes. Previous genetic studies of BD have reported several genes as potentially associated with BD. The ANK3 gene has been identified as a possible BD susceptibility gene in genome-wide association analyses.

Aims: The goal of the present study was to evaluate the association of ANK3 variants with BD in the Korean population.

Methods: Based on previous results, two single nucleotide polymorphisms (SNPs), rs1938526 and rs10994336, were selected in the ANK3 gene. The study included 287 BD patients and 340 healthy controls. Case-control association and case-control haplotype analyses of the two ANK3 variants were performed.

Results: No significant association was found of either single SNP with BD by case-control association analysis. However, rs1938526 and rs10994336 showed a significant association (overall p?=?3.6?×?10^?11; permutation p?=?0) in a case-control haplotype analysis.

Conclusions: The haplotype analysis results suggest that ANK3 variants rs1938526 and rs10994336 may confer susceptibility for BD in the Korean population. Association analysis revealed a probable genetic difference between Korean and Caucasian populations in the degree of ANK3 involvement in BD pathogenesis.     

Mental health treatment seeking among patients with OCD: impact of age of onset

Background

Several studies have described the deficits in the health care provided to persons with obsessive–compulsive disorder (OCD), however, without making any distinction between psychiatric–psychotherapeutic professionals and general practitioners or other professionals. Also, the relation between subjectively defined early signs of the disorder, diagnosis and utilization of professional help has not yet been investigated systematically. The present study addresses these questions, using a self-rating questionnaire for patients with OCD (questionnaire on the utilization of professional help by patients with OCD).

Methods

Eighty-eight patients with OCD, who came to our University Hospital Outpatient Clinic for obsessive–compulsive disorders in Leipzig, participated in the study. The questionnaire, which had been developed specially for this survey, asked study participants to remember when they had first perceived signs of their disorder and their first-time utilization of professional help.

Results

Patients with OCD and early onset of disorder sought professional help later than did patients with later onset of disorder. When professional help was utilized, it took 2 years on average before the diagnosis was made. Patients with OCD first consulted a psychiatrist or psychotherapist and not the general practitioner as their first professional contact person.

Conclusion

First signs in the early stages of OCD, particularly with an onset in childhood and adolescence have to be diagnosed at an earlier stage for appropriate treatment. Psychiatrists and psychotherapists, not primarily general practitioners, have a particularly high demand for further education about early diagnosis and treatment of OCD.     

Evidence for Association between the Brain-Derived Neurotrophic Factor Gene and Panic Disorder: A Novel Haplotype Analysis

Objective

Panic disorder (PD) is a common psychiatric disorder with a complex etiology, and several studies have suggested that it has a genetic component. Brain-derived neurotrophic factor (BDNF) is the most abundant of the neurotrophins in the brain and is recognized for its important role in the survival, differentiation and growth of neurons. Several lines of research have suggested possible associations between the BDNF gene and PD. In this study, we investigated the BDNF 196G/A (rs6265), 11757G/C (rs16917204), and 270C/T (rs56164415) single nucleotide polymorphisms (SNPs) in order to determine an association with PD. We also identified the genetic sequence associations with PD via haplotype analysis.

Methods

Participants in this study included 136 PD patients and 263 healthy controls. Male and female subjects were analyzed separately. The genotype and allele frequencies of the PD patients and controls were analyzed using χ² statistics. Frequencies and haplotype reconstructions were calculated using the SNP analyzer 2.0.

Results

We found no significant statistical differences in the genotype distributions or allele frequencies of the three tested polymorphisms between the PD and control groups. In addition, no differences were found between PD patients and the controls in either male or female subgroups. However, we found that, the frequency of the G-C haplotype for 196G/A and 11757G/C was significantly higher in PD patients than in the controls.

Conclusion

Our result suggest that patients with the G-C haplotype for 196G/A and 11757G/C may be more susceptible to the development of PD. Further studies are needed to replicate the associations that we observed.     

A novel SNP in <Emphasis Type="Italic">COMT</Emphasis> is associated with alcohol dependence but not opiate or nicotine dependence: a case control study

Background

It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated.

Methods

To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence.

Results

The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases.

Conclusions

Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.