Association analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population

Background

Abnormalities in glutaminergic neural transmission have been suggested to be involved in the pathogenesis of schizophrenia. A recent study reported that alterations in the 5-HT2A–mGluR2 complex may be involved in neural transmission in the schizophrenic cortex. In addition, methamphetamine-induced psychosis is thought to be similar to schizophrenia. Therefore, we conducted a case-control study with Japanese samples (738 schizophrenia patients, 196 methamphetamine-induced psychosis patients, and 802 controls) to evaluate the association and interaction between GRM2, HTR2A and schizophrenia.

Methods

We selected three ‘tagging SNPs’ in GRM2, and two biologically functional SNPs in HTR2A (T102C and A1438G), for the association analysis.

Results

We detected a significant association between methamphetamine-induced psychosis and GRM2 in a haplotype-wise analysis, but not HTR2A. We did not detect an association between GRM2 or HTR2A and schizophrenia. In addition, no interactions of GRM2 and HTR2A were found in methamphetamine-induced psychosis or schizophrenia. We did not detect any novel polymorphisms in GRM2 when we performed a mutation search using methamphetamine-induced psychosis samples.

Conclusion

Our results suggested that GRM2 may play a role in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia in the Japanese population. A replication study using larger samples or samples of other populations will be required for conclusive results.     

No effect of obstetric complications on basal ganglia volumes in schizophrenia

Background

Heterogeneous findings have been reported in studies of basal ganglia volumes in schizophrenia patients as compared to healthy controls. The basal ganglia contain dopamine receptors that are known to be involved in schizophrenia pathology and to be vulnerable to pre- and perinatal hypoxic insults. Altered volumes of other brain structures (e.g. hippocampus and lateral ventricles) have been reported in schizophrenia patients with a history of obstetric complications (OCs). This is the first study to explore if there is a relationship between OCs and basal ganglia volume in schizophrenia.

Methods

Thorough clinical investigation (including information on medication) of 54 schizophrenia patients and 54 healthy control subjects was undertaken. MR images were obtained on a 1.5 T scanner, and volumes of nucleus caudatus, globus pallidum, putamen, and nucleus accumbens were quantified automatically. Information on OCs was blindly collected from original birth records.

Results

Unadjusted estimates demonstrated a relationship between increasing number of OCs and larger volume of nucleus accumbens in schizophrenia patients and healthy controls. No statistically significant relationships were found between OCs and the basal ganglia volumes when controlled for intracranial volume, age, and multiple comparisons. There were no effects of typical versus atypical medication on the basal ganglia volumes. The patients with schizophrenia had larger globus pallidum volumes as compared to healthy controls, but there were no case–control differences for accumbens, putamen, or caudate volumes.

Conclusion

The present results do not support the hypothesis that OCs are related to alterations in basal ganglia volume in chronic schizophrenia.     

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population

Background

The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene.

Method

We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls.

Result

No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global χ² = 1.318, P = 0.725, df = 3).

Conclusion

Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.     

PROKR2 is associated with methamphetamine dependence in the Japanese population

Background

Many patients with drug addiction are reported to have comorbid mood disorders. One of the suggested pathophysiological mechanisms for mood disorders is disruption of circadian rhythms. Several animal studies have shown that methamphetamine altered the expression of circadian clock molecules in the brain. Therefore, it is possible that mood disorders and drug addiction have common susceptibility genes. Recently, we reported that the prokineticin 2 receptor gene (PROKR2) was associated with mood disorders including major depressive disorder and bipolar disorder in the Japanese population. In the present study, therefore, we conducted an association analysis of tagging SNPs in PROKR2 with Japanese methamphetamine dependence patients.

Methods

Using five tagging SNPs in PROKR2, we conducted a genetic association analysis of case–control samples (199 methamphetamine dependence patients and 337 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients.

Results

We detected a significant association between PROKR2 and methamphetamine dependence patients in allele/genotype-wise and haplotype-wise analysis.

Conclusion

Our results suggest that PROKR2 may play a role in the pathophysiology of methamphetamine dependence in the Japanese population. However, because we did not perform a mutation scan of PROKR2, a replication study using a larger sample may be required for conclusive results.     

Association analysis of Group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population

Background

Several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BP). Preclinical antidepressant effects were also reported for group II metabotropic glutamate receptor (Group II mGluRs) antagonists show dose-dependent antidepressant-like effects in murine models of depression. Also, it has been suggested that abnormalities in the hypothalamic-pituitary-adrenal axis and serotonergic neural transmission are important mechanisms in the pathophysiology of mood disorders. Group II mGluRs play an important role in regulating the function of these mechanisms. From these results, it has been suggested that abnormalities in Group II mGluRs might be involved in the pathophysiology of mood disorders, including MDD) and BP, and may influence the clinical response to treatment with SSRIs in MDD. Therefore, we studied the association between Group II mGluR genes (GRM2 and GRM3) and mood disorders and the efficacy of fluvoxamine treatment in Japanese MDD patients.

Materials and methods

Using three tagging SNPs in GRM2 and an SNP (rs6465084) reported functional variant in GRM3, we conducted a genetic association analysis of case-control samples (325 MDD patients, 155 BP patients and 802 controls) in the Japanese population. In addition, we performed an association analysis of GRM2 and GRM3 and the efficacy of fluvoxamine treatment in 117 Japanese patients with MDD. The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks.

Results

We found an association between rs6465084 in GRM3 and MDD in the allele-wise analysis after Bonferroni's correction (P-value = 0.0371). However, we did not find any association between GRM3 and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analysis. We also did not detect any association between GRM2 and MDD, BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise or haplotype-wise analysis.

Discussion

We detected an association between only one marker (rs6465084) in GRM3 and Japanese MDD patients. However, because we did not perform an association analysis based on LD and a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.     

Effects of common <Emphasis Type="Italic">GRM5</Emphasis> genetic variants on cognition,hippocampal volume and mGluR5 protein levels in schizophrenia

GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippocampal volume, and hippocampal mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were examined among individuals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippocampal volume relative to healthy controls of the same genotype (?12.3%); this effect was exaggerated in males with schizophrenia (?15.6%). For rs3824927, compared to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippocampal postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 were associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they did not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.     

A functional polymorphism in estrogen receptor alpha gene is associated with Japanese methamphetamine induced psychosis

Background

A recent study reported an association between rs2234693, which influences enhancer activity levels in estrogen receptor alpha gene (ESR1), and schizophrenia. This study reported that schizophrenic patients with the CC genotype have significantly lower ESR1 mRNA levels in the prefrontal cortex than patients with other genotypes. The symptoms of methamphetamine induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an association analysis of rs2234693 with Japanese methamphetamine induced psychosis patients.

Method

Using rs2234693, we conducted a genetic association analysis of case-control samples (197 methamphetamine induced psychosis patients and 197 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine induced psychosis patients.

Results

We detected a significant association between ESR1 and methamphetamine induced psychosis patients in allele/genotype-wise analysis. For further interpretation of these associations, we performed single marker analysis of subjects divided by sex. Rs2234693 was associated with male methamphetamine induced psychosis.

Discussion

Our results suggest that rs2234693 in ESR1 may play a role in the pathophysiology of Japanese methamphetamine induced psychosis patients.     

A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes

Background

The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1.

Methods

We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case–control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1.

Results

Case–control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p = 0.01, Odds Ratio = 1.5, 95% Confidence Interval = 1.1–2.2), and the intergenic rs2242592 (p = 2 · 10^− 4, OR = 1.8, 95%CI = 1.3–2.5). A significant SNP–SNP interaction was also found (p < 10^− 5, OR = 2.0, 95%CI = 1.6–2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage.

Conclusions

Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.     

Cerebral cortical thickness and a history of obstetric complications in schizophrenia

Introduction

Magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have thinner brain cortices compared with healthy control subjects. Neurodevelopment is vulnerable to obstetric complications (OCs) such as hypoxia and birth trauma, factors that are also related to increased risk of developing schizophrenia. With the hypothesis that OCs might explain the thinner cortices found in schizophrenia, we studied patients with schizophrenia and healthy controls subjects for association between number and severity of OCs and variation in cortical thickness.

Methods

MRI scans of 54 adults with schizophrenia or schizoaffective disorder and 54 healthy controls were acquired at Karolinska Institutet, Stockholm, Sweden. Measures of brain cortical thickness were obtained using automated computer processing (FreeSurfer). OCs were assessed from obstetric records and scored blindly according to the McNeil–Sjöström scale. At numerous cortical locations, putative effects of OCs on cortical thickness variation were tested for each trimester, for labour, for composite OC scores, severe OC scores, and hypoxia scores among patients and controls separately.

Results

Number and severity of OCs varied among both patient and control subjects but were not associated with cortical thickness in either of the groups. Patients demonstrated thinner brain cortices but there were no significant differences in number and severity of OC scores across groups.

Conclusion

In the present study, number and severity of obstetric complications were not associated with brain cortical thickness, in patients with schizophrenia or in healthy control subjects. The thinner brain cortices found in patients with schizophrenia were not explained by a history of OCs.     

A genetic association study of D-dimer levels with 50 K SNPs from a candidate gene chip in four ethnic groups

Introduction

D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.

Materials and Methods

We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.

Results

Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0 × 10^− 6. The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer.

Conclusions

Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.     

Lack of association between translin-associated factor X gene (TSNAX) and methamphetamine dependence in the Japanese population

Objectives

Recently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence.

Methods

We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database.

Results

rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P-value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152).

Conclusion

Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results.     

VKORC1 and CYP2C9 genotype distribution in Asian countries

Background

Warfarin is the most widely used anticoagulant all over the world for prevention and treatment of different thrombotic conditions. Polymorphisms in two genes i.e. CYP2C9 (Cytochrome P450 2C9) and VKORC1 (Vitamin K epoxide reductase complex subunit 1) play a major role in warfarin dose variation and its related adverse effects. Different ethnic groups have shown significant differences in dose requirement.

Method

A systematic electronic search was carried out in PUBMED and ScienceDirect using different key words like, ‘warfarin’, ‘CYP2C9’, ‘VKORC1’, ‘pharmacokinetics’, ‘metabolites’ and ‘genetic’. Till date, data from 15 Asian countries for CYP2C9 genotypes and 14 Asian countries for VKORC1 genotypes could be retrieved.

Results

Approximately 90% of the subjects from East Asian countries were found to be carriers for VKORC1 1639 ‘A’ or 1173 ‘T’ allele (associated with low dose warfarin), while the prevalence of these alleles in the rest of the Asian countries (except Iran) i.e. South, South East, West and Central Asia ranged between 14 and 80%. Interestingly, an increase in carrier rate for CYP2C9 *2 or *3 alleles was observed as we move from East to West Asia and an opposite trend was observed with VKORC1 1639 ‘A’ or 1173 ‘T’ alleles. Countries like Iran, Oman, India and Russia showed a drastic variation in the distribution pattern of these genotypes from that of the neighboring countries.

Conclusion

The analysis further highlights the importance of genotype based warfarin dosing in each country. Since many Asian countries are still underrepresented in pharmacogenomic research, addition of data from these underrepresented countries will be beneficial for safe warfarin dosing in these patients.     

The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and antisocial personality disorder in male heroin-dependent Chinese subjects

Objective

To explore the association between the 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR polymorphisms with comorbidity of antisocial personality disorder in male heroin-dependent patients.

Subjects and methods

In case control study, we compared the polymorphic distributions of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR in 588 male heroin-dependent patients (including 311 patients with antisocial personality disorder and 277 patients without antisocial personality disorder) and 194 normal males by genotypes, alleles, and interaction between genes.

Results

Between male heroin-dependent patients with antisocial personality disorder and normal males, and between male heroin-dependent patients with and without antisocial personality disorder, the distributions of 5-HTTVNTR polymorphic genotypes and alleles were in statistical significance. Individuals carrying 10R allele were in higher risk of the comorbidity of antisocial personality disorder and heroin dependence. By MDR analyses, the interaction between 5-HTTVNTR and DATVNTR was close to statistical significance in predicting the risk of antisocial personality disorder in male heroin dependent patients. In male heroin dependent patients, individuals carrying 5-HTTVNTR 10R allele or/and DATVNTR 9R allele were in higher risks of co-occurring antisocial personality disorder, while individuals with 5-HTTVNTR 12R/12R and DATVNTR 10R/10R genotypes together were in lower risks of antisocial personality disorder.

Conclusion

5-HTTVNTR, and the interaction between 5-HTTVNTR and DATVNTR may be associated with the comorbidity of antisocial personality disorder in male heroin-dependent patients.     

TPH2 is not a susceptibility gene for suicide in Japanese population

Background

Serotonergic systems mediate a control of aggression and/or impulsivity in human and are suggested to be involved in suicidal behavior. The newly identified neuronal tryptophan hydroxylase isoform 2 (TPH2), the rate-limiting enzyme in serotonin synthesis, represents a prime candidate in numerous genetic association analyses of suicidal behavior; however, the results are still inconclusive. The discrepancy may result from the heterogeneity of pathogenesis of suicidal behavior and/or methodological mismatches. We, therefore, attempted to replicate the association of TPH2 gene with suicide using a case-control study of 234 completed suicides and 260 control subjects in Japanese population.

Methods

We genotyped 15 tagging-single nucleotide polymorphisms (SNPs) including 4 SNPs, which were previously reported to be associated with suicidal behavior, using the TaqMan probe assays and the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method.

Results

We found no significant differences in genotypic distributions (uncorrected p = 0.06–0.98) or allelic frequencies (uncorrected p = 0.09–0.95) of the fifteen SNPs between the completed suicides and control groups. Haplotypes constructed with these SNPs were also not associated with suicide (uncorrected p = 0.03–0.96 and corrected p = 0.20–1.00). Even when we took sex and suicidal methods (violent or non-violent) into account for the analyses, no significant differences in genotypic distributions, allelic/haplotypic frequencies were found in the two groups.

Conclusion

Our results suggest that the common SNPs and haplotypes of the TPH2 gene are unlikely to contribute to the genetic susceptibility to suicidal behavior in Japanese population.     

Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population

Objective

CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder.

Methods

We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G).

Results

There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive.

Conclusion

We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required.     

Genotyping Sleep Disorders Patients

Objective

The genetic susceptibility factors underlying sleep disorders might help us predict prognoses and responses to treatment. Several candidate polymorphisms for sleep disorders have been proposed, but there has as yet inadequate replication or validation that the candidates may be useful in the clinical setting.

Methods

To assess the validity of several candidate associations, we obtained saliva deoxyribonucleic acid (DNA) samples and clinical information from 360 consenting research participants who were undergoing clinical polysomnograms. Ten single nucleotide polymorphisms (SNPs) were genotyped. These were thought to be related to depression, circadian sleep disorders, sleep apnea, restless legs syndrome (RLS), excessive sleepiness, or to slow waves in sleep.

Results

With multivariate generalized linear models, the association of TEF rs738499 with depressive symptoms was confirmed. Equivocal statistical evidence of association of rs1801260 (the C3111T SNP in the CLOCK gene) with morningness/eveningness and an association of Apolipoprotein E (APOE) rs429358 with the Epworth Sleepiness Scale (ESS) were obtained, but these associations were not strong enough to be of clinical value by themselves. Predicted association of SNPs with sleep apnea, RLS, and slow wave sleep were not confirmed.

Conclusion

The SNPs tested would not, by themselves, be of use for clinical genotyping in a sleep clinic.     

Resequencing of VKORC1, CYP2C9 and CYP4F2 genes in Italian patients requiring extreme low and high warfarin doses

Purpose

The aim of the present study was to investigate the genetic variability of VKORC1, CYP2C9 and CYP4F2 genes in patients who required a very low and high warfarin dose, in order to identify novel variants that could help to explain the particular extreme dose requirements.

Methods

Among patients followed and treated with warfarin at the Center of Haemostasis and Thrombosis of the PTV, we selected twelve patients showing a high divergence from warfarin standard doses required to achieve the therapeutic effect.All VKORC1, CYP2C9 and CYP4F2 coding regions, 3’ and 5’ UTR and exon/intron boundaries were analyzed by direct sequencing.

Results

The 1173T and -1639A allele variants in VKORC1 gene, associated with warfarin sensitivity, were present, as expected, mostly in low dose patients while 3730A allele, linked to warfarin resistance, has been found only in high dose patients. Interestingly, we found that three out of six low dose subjects presented CYP2C9*3/*3 homozygous genotype, very rare in Caucasians.Besides these common polymorphisms, we identified 5 SNPs in CYP2C9 gene and 19 SNPs in CYP4F2 gene. Among these, all polymorphisms identified in CYP2C9 gene were present only in low dose patients and three of them resulted in linkage with CYP2C9*2 and CYP2C9*3. Regarding CYP4F2 SNPs, we did not observe differences between the high and low dose patients. At the end, the whole sequencing did not reveal any novel polymorphism/mutation.

Conclusion

Further studies are required to identify other genetic factors contributing to extreme warfarin requirement.     

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.     

The relationship between symptom severity and regional cortical and grey matter volumes in schizophrenia

Objective

To investigate the relationship between symptom severity and cortical and grey matter volumes in schizophrenia.

Method

Fifty-three outpatients with schizophrenia were assessed by the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. Symptoms were grouped into five factors (negative, relational, inattention, disorganization, and reality distortion). Cortical and lobar grey matter volumes within all regions of the brain were obtained from magnetic resonance images using two independent software tools. The relationships between brain volumes and symptom factors were analyzed by partial correlations controlling for age, gender, dose and type of antipsychotic medication, and intracranial volume.

Results

Negative symptoms were generally associated with larger cortical volumes in all regions of the brain, and the relational and inattention factors were associated with larger frontal grey matter volumes. The reality distortion factor was associated with smaller cortical volumes throughout the brain and with smaller frontal and temporal grey matter volumes.

Conclusion

Differential contribution of positive and negative symptoms to variation in cortical and grey matter volumes indicates separate neurobiological mechanisms underlying the two major symptom domains in schizophrenia.