Genome-wide association studies of maximum number of drinks

Maximum number of drinks (MaxDrinks) defined as “Maximum number of alcoholic drinks consumed in a 24-h period” is an intermediate phenotype that is closely related to alcohol dependence (AD). Family, twin and adoption studies have shown that the heritability of MaxDrinks is approximately 0.5. We conducted the first genome-wide association (GWA) study and meta-analysis of MaxDrinks as a continuous phenotype. 1059 individuals were from the Collaborative Study on the Genetics of Alcoholism (COGA) sample and 1628 individuals were from the Study of Addiction – Genetics and Environment (SAGE) sample. Family sample with 3137 individuals was from the Australian twin-family study of alcohol use disorder (OZALC). Two population-based Caucasian samples (COGA and SAGE) with 1 million single-nucleotide polymorphisms (SNPs) were used for gene discovery and one family-based Caucasian sample was used for replication. Through meta-analysis we identified 162 SNPs associated with MaxDirnks (p < 10⁻⁴). The most significant association with MaxDrinks was observed with SNP rs11128951 (p = 4.27 × 10⁻⁸) near SGOL1 gene at 3p24.3. Furthermore, several SNPs (rs17144687 near DTWD2, rs12108602 near NDST4, and rs2128158 in KCNB2) showed significant associations with MaxDrinks (p < 5 × 10⁻⁷) in the meta-analysis. Especially, 8 SNPs in DDC gene showed significant associations with MaxDrinks (p < 5 × 10⁻⁷) in the SAGE sample. Several flanking SNPs in above genes/regions were confirmed in the OZALC family sample. In conclusions, we identified several genes/regions associated with MaxDrinks. These findings can improve the understanding about the pathogenesis of alcohol consumption phenotypes and alcohol-related disorders.     

Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: A meta-analysis of double-blind randomized placebo-controlled trials

Background

We performed an updated meta-analysis of noradrenalin reuptake inhibitor (NRI) augmentation therapy in patients with schizophrenia treated with antipsychotics based on a previous meta-analysis (Singh et al.).

Methods

PubMed, Cochrane Library databases, and PsycINFO citations were searched from their inception to June 10, 2013 without language restrictions. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing NRI augmentation therapy with placebo. The outcome measure for efficacy was the psychopathology of schizophrenia and the measures for safety were discontinuation rate and several side effects. We used standardized mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous variables, with their 95% confidence intervals (CIs). A random-effects model was used.

Results

Nine studies (4 atomoxetine studies, 3 reboxetine studies, 1 reboxetine–betahistine combination study and 1 mazindol study, total n = 298) were identified. No statistically significant effects of NRI augmentation therapy on overall (p = 0.90), positive (p = 0.81), and negative (p = 0.89) symptoms were found. NRI augmentation therapy was marginally superior to placebo for efficacy of depressive symptoms (SMD = −1.08, p = 0.05). Dropout due to all-cause (p = 0.70), inefficacy (p = 0.64), or adverse events (p = 0.18) was similar in both groups. NRI augmentation therapy showed a significantly lower increase or larger reduction in body weight than placebo (SMD = −0.47, p = 0.03). Reboxetine augmentation was associated with less weight gain that placebo in antipsychotic treated schizophrenia patients (SMD = −0.78, p = 0.0001).

Conclusion

NRIs may exert an effect on depressive symptoms, and seem to be well-tolerated treatments.     

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.     

Promoter specific methylation of the dopamine transporter gene is altered in alcohol dependence and associated with craving

Dopaminergic neurotransmission plays a crucial role in the genesis and maintenance of alcohol dependence. Epigenetic regulation via promoter specific DNA methylation of the dopamine transporter gene (DAT) may influence altered dopaminergic neurotransmission in alcoholism. Aim of the present study was to investigate DNA promoter methylation of DAT in early alcohol withdrawal and in relation to alcohol craving. We analyzed blood samples of 76 patients admitted for detoxification treatment and compared them to 35 healthy controls. Methylation specific quantitative real-time PCR was used to measure the promoter specific DNA methylation of the dopamine transporter. We assessed the extent of alcohol craving using the obsessive compulsive drinking scale (OCDS). Compared to healthy controls we found a significant hypermethylation of the DAT-promoter (Mann-Whitney U-test: p = 0.001). Ln-transformed methylation of the DAT-promoter was negatively associated with the OCDS (linear regression: Beta = −0.275, p = 0.016), particularly with the obsessive subscale (Beta = −0.300, p = 0.008). Findings of the present study show that the epigenetic regulation of the DAT-promoter is altered in patients undergoing alcohol withdrawal. Furthermore, hypermethylation of the DAT-promoter may play an important role in dopaminergic neurotransmission and is associated with decreased alcohol craving.     

Polymorphisms in PDLIM5 gene are associated with alcohol dependence,type 2 diabetes,and hypertension

The PDZ and LIM domain 5 (PDLIM5) gene may play a role in alcohol dependence (AD), bipolar disorder, and major depressive disorder; however, no study has identified shared genetic variants within PDLIM5 gene among AD, type 2 diabetes (T2D), and hypertension. This study investigated the association of 72 single nucleotide polymorphism (SNPs) with AD (1066 AD cases and 1278 controls) in the Study of Addiction - Genetics and Environment (SAGE) sample and 47 SNPs with T2D (878 cases and 2686 non-diabetic) and hypertension (825 cases and 2739 non-hypertensive) in the Marshfield sample. Multiple logistic regression models in PLINK software were used to examine the associations of genetic variants with AD, T2D, and hypertension and SNP x alcohol consumption interactions for T2D and hypertension. Twenty-five SNPs were associated with AD in the SAGE sample (p < 0.05); rs1048627 showed the strongest association with AD (p = 5.53 × 10⁻⁴). Of the 25 SNPs, 5 SNPs showed associations with both AD in the SAGE sample and T2D in the Marshfield sample (top SNP rs11097432 with p = 0.00107 for T2D and p = 0.0483 for AD) while 6 SNPs showed associations with both AD in the SAGE sample and hypertension in the Marshfield sample (top SNP rs12500426 with p = 0.0119 for hypertension and p = 1.51 × 10⁻³ for AD). SNP (rs6532496) showed significant interaction with alcohol consumption for hypertension. Our results showed that several genetic variants in PDLIM5 gene influence AD, T2D and hypertension. These findings offer the potential for new insights into the pathogenesis of AD, T2D, and hypertension.     

Genetic variants of D2 but not D3 or D4 dopamine receptor gene are associated with rapid onset and poor prognosis of methamphetamine psychosis

D2-like receptors are key targets for methamphetamine in the CNS, and their activation is an initial and indispensable effect in the induction of dependence and psychosis. It is possible that genetic variants of D2-like receptors may affect individual susceptibility to methamphetamine dependence and psychosis. To test this hypothesis, 6 putatively functional polymorphisms of D2-like receptors, −141C Ins/Del, Ser311Cys and TaqIA of the DRD2 gene, Ser9Gly of the DRD3 gene, and −521C>T and a variable number of tandem repeats in exon 3 of the DRD4 gene, were analyzed in 202 patients with methamphetamine dependence and/or psychosis and 243 healthy controls in a Japanese population. No polymorphism examined showed significant association with methamphetamine dependence, but two polymorphisms of DRD2 were associated with the clinical course and prognosis of methamphetamine psychosis. The A1/A1 homozygote of DRD2 was a negative risk factor for a poorer prognosis of psychosis that continues for more than 1 month after the discontinuance of methamphetamine abuse and the beginning of treatment with neuroleptics (p = 0.04, odds ratio (OR) = 0.42, 95% CI; 0.27–0.65) and the complication of spontaneous relapse of methamphetamine psychosis after remission (p = 0.014, OR = 0.34, 95% CI; 0.22–0.54). The genotype of −141C Del positive (Del/Del and Del/Ins) was at risk for rapid onset of methamphetamine psychosis that develops into a psychotic state within 3 years after initiation of methamphetamine abuse (p = 0.00037, OR = 3.62, 95% CI 2.48–5.28). These findings revealed that genetic variants of DRD2, but not DRD3 or DRD4, confer individual risks for rapid onset, prolonged duration, and spontaneous relapse of methamphetamine psychosis.     

Magnetic resonance imaging assessment of cardiac dysfunction in δ-sarcoglycan null mice

Delta-sarcoglycan (δ-sarcoglycan) null, Scgd^−/−, mice develop cardiac and skeletal muscle histopathological alterations similar to those in humans with limb-girdle muscular dystrophy. The objective of this study was to assess the feasibility of using MRI to investigate cardiac dysfunction in Scgd^−/− mice. Cardiac MRI of 8 month old Scgd^−/− and wild type (WT) mice was performed. Compared to WT, Scgd^−/− mice had significantly lower LV ejection fraction (44 ± 5% vs. 66 ± 4%, p = 0.014), lower RV ejection fraction (25 ± 2% vs. 51 ± 3%, p < 0.001) lower myocardial circumferential strain, (15.0 ± 0.3% vs. 16.9 ± 0.3%, p = 0.007) and RV dilatation (54 ± 3 μL vs. 40 ± 3 μL, p = 0.007). The regional circumferential strain also demonstrated significant temporal dyssynchrony between opposing regions of the Scgd^−/− LV. Our results demonstrate severe cardiac dysfunction in Scgd^−/− mice at 8 months. The study identifies a set of non-invasive markers that could be used to study efficacy of novel therapeutic agents in dystrophic mice.     

Differential role of serotonergic polymorphisms in alcohol and heroin dependence

Background

Twin studies suggest that genetic factors account for 40–60% of the variance in alcohol dependence. It has been stated that different drug dependencies may have unique genetic influences. Alterations in serotonin availability and function can affect drinking behaviour. This study aimed to investigate whether three serotonergic polymorphisms (HTR2A A-1438G (rs6311), and SCL6A4 5-HTTLPR and STin2 VNTR) were associated with alcohol dependence, and, whether the serotonergic polymorphisms played a similar role in conferring vulnerability in alcohol and heroin dependence.

Methods

165 alcohol dependent patients, 113 heroin dependent patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods.

Results

Genotypic frequencies of the A-1438G, 5-HTTLPR, and STin2 VNTR polymorphisms did not differ significantly across the three groups. None of the three polymorphisms contributed to distinguishing alcoholic patients from healthy controls. There was an excess of −1438G and 5-HTTLPR L carriers in alcoholic patients in comparison to the heroin dependent group (OR (95% CI) = 1.98 (1.13–3.45) and 1.92 (1.07–3.44), respectively). The A-1438G and 5-HTTLPR polymorphisms also interacted in distinguishing alcohol from heroin dependent patients (Wald (df) = 10.21 (4), p = 0.037). The association of −1438A/G with alcohol dependence was especially pronounced in the presence of 5-HTTLPR S/S, less evident with 5-HTTLPR L/S and not present with 5-HTTLPR L/L. SCL6A4 polymorphism haplotypes were similarly distributed in all three groups.

Conclusions

Our data do not support a role of serotonergic polymorphisms in alcohol dependence but suggest a differential genetic background to alcohol and heroin dependence.     

Influence of multisystemic affection on health-related quality of life in patients with myotonic dystrophy type 1

Aim

To assess health-related quality of life (HRQoL) in patients with DM1, to identify muscular, multisystemic, central and social factors that may affect QoL and to define a DM1 patient in risk of poor QoL.

Patients and method

This cross-sectional study comprised 120 DM1 consecutive patients. The following scales were used: Multidimensional Scale of Perceived Social Support (MSPSS), Muscular Impairment Rating Scale (MIRS), battery of neuropsychological tests, acceptance of illness scale (AIS), Hamilton rating scale for depression (Ham-D), Krupp's Fatigue Severity Scale (FSS), Daytime Sleepiness Scale (DSS) and SF-36 questionnaire.

Results

HRQoL was impaired in DM1 patients in both physical and mental domains (PCS was 41.8 ± 23.5, MCS 47.0 ± 24.3 and total SF-36 score 45.6 ± 24.0). The most significant factors correlating with better SF-36 total score were younger age (β = −0.45, p < 0.001), shorter duration of disease (β = −0.27, p = 0.001), higher education (β = 0.20, p = 0.009), less severe muscular weakness (β = −0.52, p < 0.001), normal swallowing (β = 0.22, p = 0.005), absence of fainting (β = 0.31, p = 0.002), absence of snoring (β = 0.21, p = 0.036), better acceptance of disease (β = −0.17, p = 0.036), lower depressiveness (β = −0.46, p = 0.001), lower fatigue (β = −0.32, p = 0.001), absence of cataract (β = −0.21, p = 0.034), absence of kyphosis (β = 0.31, p = 0.004) and absence of constipation (β = 0.24, p = 0.016). Second linear regression analysis revealed that depressed (β = −0.38, p < 0.001) and elder patients (β = −0.27, p = 0.007) and as well as those with poor acceptance of illness (β = −0.21, p = 0.006) were in especially higher risk of having poor HRQoL (R² = 0.68).

Conclusion

We identified different central, social, muscular, cardiorespiratory and other factors correlating with HRQoL. It is of great importance that most of these factors are amenable to treatment.     

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.     

HLA class II alleles and multiple sclerosis in Tunisian patients

Objective

The aim of our study was to investigate the association of HLA-DRB1 and -DQB1 alleles with multiple sclerosis (MS) in a Tunisian population and their effect on age at onset and disease severity.

Methods

58 MS patients and 105 healthy controls were genotyped for HLA class II alleles by PCR-SSP technique.

Results

An association of MS with HLA-DRB1*15 was found (14.7% vs 3.8%, OR (95% CI) = 4.34 (1.69–11.39), p_c = 2.5 × 10⁻³) after Bonferroni's correction. Moreover, the DRB1*15–DQB1*06 (13.8% vs 2.8%, OR (95% CI) = 5.44 (1.92–17.41), p_c = 1.1 × 10⁻³) and DRB1*04–DQB1*04 (8.6% vs 1.9%, OR (95% CI) = 4.86 (1.36–21.62), p_c = 0.028) haplotypes were found to confer a susceptibility to multiple sclerosis.

Conclusion

To our knowledge, this is the first study performed to analyze the association of HLA-DRB1/DQB1 alleles on MS susceptibility in Tunisia. The modern Tunisian gene pool shows some degree of heterogeneity and reflects a significant gene flow from Mediterranean regions.     

Facteurs associés aux réadmissions psychiatriques des patients hospitalisés pour la première fois à Bingerville en 2001 (Cote d’Ivoire)

Objective

To ascertain the factors related to patients’ psychiatric readmissions at Bingerville.

Patients and method

It was a case-control study built on 436 files of patients who had been hospitalized for the first time in 2001 at Bingerville's psychiatric hospital. We called readmission all rehospitalization arisen 15 days after the end of the previous hospital stay. Sociodemographic and clinical characteristics of the patients who had been readmitted for at least a fold within 1st January 2001 and 31st December 2006 were compared to those who had not been readmitted during this period, by using the Chi-square test.

Results

Patients admitted for the first time at Bingerville psychiatric hospital were in majority less than 44 years old (87.8%) with mean age at 31.1 ± 10.9 years. More than half of them, had male gender (61.9%), was single or widowed or separated (70.6%), without a kid (55.5%). Numerous of them were not educated above secondary school (95.4%). In these first admitted patients, 50.9% did not earn a wage, 68.8% lived in Abidjan. Those who had both their mother and father alive represented 53.9% of the study sample. About two-third of the patients were younger in their siblings, as well in father's children as in mother's. Regarding the clinical features, schizophrenia and other psychotic disorders (59.2%) were the most frequent diagnosis, followed by mood disorders (19.0%). These mental disorders started during the month before first psychiatric hospitalization at Bingerville (47.2%). The majority (74.5%) of these patients were hospitalized 30 days at most. They were discharged with medical advice (85.8%) and less than two drugs prescribed (66.3%). The aftercare treatment did not last more than 26 weeks for most of the patients (79.6%). Readmission occurred at least a fold in 22.5% of the subjects, in majority during the first 2 years after being discharged in 2001 (68.4%). Patients characteristics related to readmission during the 6 years of study period were: being less than 21 years old (p = 9 × 10⁻⁴), younger in the siblings of mother's children (p = 10⁻³), having both mother and father alive (p = 3 × 10⁻³), a mood disorder diagnosis (p = 0.046) and a length of aftercare treatment exceeding 26 weeks (p = 4 × 10⁻³).

Conclusion

When they are repeated and closer, readmissions can worsen patients’ social reinsertion. The knowledge of factors related to these rehospitalizations is useful to prevent this consequence.     

The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis

Background

The inherited JAK2 46/1 haplotype is strongly associated with the development of myeloproliferative neoplasms (MPNs), and its increased frequency has also been reported in splanchnic venous thrombosis (SVT). In the present study, the role of the JAK2 46/1 haplotype in non-splanchnic venous thrombosis (non-SVT) was investigated.

Methods and Results

We genotyped 438 patients with non-SVT, 226 patients with MPNs and 459 healthy controls for three single nucleotide polymorphisms (SNPs) which tag the JAK2 46/1 haplotype (rs12342421 G > C, rs12343867 T > C and rs10974944 C > G). We found statistically significant association of the rs12342421 GC + CC genotypes (OR = 1.40; p = 0.023) and the rs12343867 TC + CC genotypes (OR = 1.83; p = 7.02x10^- 5) with non-SVT. We also found that the CC haplotype of these two SNPs was associated with an increased risk of the disease (OR = 1.68; p = 0.009). Stratification analysis indicated that the observed association of the JAK2 46/1 haplotype with non-SVT was probably largely free of confounding effect of thrombophilic risk factors. In addition, we established a strong association of SNPs rs12342421 and rs10974944 and their CG haplotype with MPNs and with JAK2 V617F-positive MPNs.

Conclusions

This study provides statistical evidence that SNPs rs12342421 and rs12343867 are associated with an increased risk of non-SVT. Consistently, haplotypes of the SNPs were also associated with non-SVT risk, suggesting that inherited genetic variation in the JAK2 gene may play a role in the pathogenesis of non-SVT. Furthermore, the reported associations of the JAK2 46/1 haplotype with MPNs as well as with the occurrence of the JAK2 V617F mutation in MPNs were confirmed.     

NTM and NR3C2 polymorphisms influencing intelligence: family-based association studies

Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p < 10^− 3) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p = 0.000764) and NR3C2 at 4q31.1 (rs3846329, p = 0.000675) were two novel genes which have not been associated with IQ in other studies. It has been reported that NTM might play a role in late-onset Alzheimer disease while NR3C2 may be associated with cognitive function and major depression. The associations of these two genes were well-replicated by single-marker and haplotype analyses in the IMAGE sample. In conclusion, our findings provide evidence that chromosome regions of 11q25 and 4q31.1 contain genes affecting IQ. This study will serve as a resource for replication in other populations.     

Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: Data from an association study

Objective

To investigate the association between dopaminergic polymorphisms [DRD2 −141C Ins/Del, DRD3 Ser9Gly, and SLC6A3 VNTR] and schizophrenia.

Methods

Two hundred and eighty-eight outpatients with schizophrenia (DSM-IV criteria) [mean age (SD) = 36.4 (12.4), 60.1% males] and 421 unrelated healthy controls [mean age (SD) = 40.6 (11.3), 51.3% males] from a homogeneous Spanish Caucasian population were genotyped using standard methods.

Results

There was a significant difference in genotype distribution for the DRD2 −141C Ins/Del polymorphism [(χ² (2) = 12.35, corrected p = 0.012]. The − 141C Del allele was more common in patients than in controls [0.19 vs. 0.13; χ² (1) = 9.14, corrected p = 0.018, OR (95% CI) = 1.57 (1.17–2.10)]. Genotype and allele distributions for DRD3 Ser9Gly and SLC6A3 VNTR polymorphisms were similar in both groups. However, there was tentative evidence of an interaction effect between DRD3 Ser9Gly and SLC6A3 VNTR [Wald = 9.56 (4), p = 0.049]. Compared to the SLC6A3 10/10 genotype category, the risk of schizophrenia was halved among those with 9/10 [OR = 0.51 (95% CI = 0.30–0.89), p = 0.017]. This protective effect was only present in combination with DRD3 Ser/Ser genotype because of the significant interaction between 9/10 and both Ser/Gly [OR = 2.45 (95% CI = 1.16–5.17), p = 0.019] and Gly/Gly [OR = 3.80 (95% CI = 1.24–11.63), p = 0.019].

Conclusions

This study provides evidence that a genetic variant in the DRD2 gene and possible interaction between DRD3 and SLC6A3 genes are associated with schizophrenia. These findings warrant examination in replication studies.     

Insight, dépression, estime de soi et satisfaction de vie chez des personnes souffrant de schizophrénie

Recent studies on insight in schizophrenia, mainly english-speaking, have shown that denial of mental disorder (lack of insight) is connected with a less good compliancy with treatment. Consequently, therapies, which increase insight, develop currently (psychoeducation and information of patients, for instance). Nonetheless, certain studies concluded that awareness of mental disorder has a negative effect on psychological dimensions like humor, self-esteem and quality of life. So we realize a pilot-study on 20 schizophrenic subjects (DSM-IV) (15 men and five women including 13 full-time inpatients and 7 days in-patients) from 22 to 61 years (m = 41.75; σ = 11.94). The aim of the study was to measure insight (IS and Q8), depressive experience (SCL90-R and CDSS), self-esteem (SEI) and satisfaction with life (SWLS), then to calculate correlation between insight and the three other dimensions. Data analysis confirmed a strong link between insight and deterioration of self-esteem (r = −0.6922; p = 0.001) and with an increase of depressive experience (r = 0.8134; p = 0.000 with SCL90-R and r = 0.6041; p = 0.006 with CDSS). Satisfaction with life is not significantly correlated with insight (r = −0.2047; p = 0.401). Those results show that clinicians must take into account the depressive effect of therapeutic strategies aiming at an increase in insight.     

Parent–child DRD4 genotype as a potential biomarker for oppositional,anxiety, and repetitive behaviors in children with autism spectrum disorder

The primary objective of the present study was to examine whether a combination of parent-child DRD4 genotypes results in more informative biomarkers of oppositional, separation anxiety, and repetitive behaviors in children with autism spectrum disorder (ASD). Based on prior research indicating the 7-repeat allele as a potential risk variant, participants were sorted into one of four combinations of parent–child genotypes. Owing to the possibility of parent-of-origin effects, analyses were conducted separately for mother–child (MC) and father–child (FC) dyads. Mothers completed a validated DSM-IV-referenced rating scale. Partial eta-squared (ηp²) was used to determine the magnitude of group differences: 0.01–0.06 = small, 0.06–0.14 = moderate, and > 0.14 = large. Analyses indicated that children in MC dyads with matched genotypes had the least (7−/7−) and most (7+/7+) severe mother-rated oppositional-defiant (ηp² = 0.11) and separation anxiety (ηp² = 0.19) symptoms. Conversely, youths in FC dyads with matched genotypes had the least (7−/7−) and most (7+/7+) severe obsessive-compulsive behaviors (ηp² = 0.19) and tics (ηp² = 0.18). Youths whose parents were both noncarriers had less severe tics than peers with at least one parental carrier, and the effect size was large (ηp² = 0.16). There was little evidence that noncarrier children were rated more severely by mothers who were carriers versus noncarriers. Transmission Disequilibrium Test analyses provided preliminary evidence for undertransmission of the 2-repeat allele in youths with more severe tics (p = 0.02). Parent genotype may be helpful in constructing prognostic biomarkers for behavioral disturbances in ASD; however, findings are tentative pending replication with larger, independent samples.     

Impaired fibrin gel permeability by high homocysteine levels

Mechanisms involved in the relationship between hyperhomocysteinemia and thrombosis are still unclear. In previous reports we have shown that high homocysteine concentrations led to more compact and branched fibrin networks than controls. These clots showed an impaired lysis associated to their architecture. The aim of this study was to evaluate the effects of homocysteine on permeation of clots obtained from plasma and purified systems.Fibrin gels were prepared with normal plasma incubated with homocysteine and, in the purified systems, with fibrinogen and factor XIII treated with the amino acid. Permeability constants (K_s) were determined through flow measurements.Linear regression curve between K_s values and homocysteine levels in the plasmatic assays showed a negative correlation coefficient, r = - 0.997 (p = 0.003). K_s of fibrin gels obtained from purified systems with fibrinogen incubated with homocysteine was (7.07 ± 0.27) × 10^- 9 cm², control was (11.40 ± 0.37) × 10^- 9 cm² (n = 3; p < 0.01). K_s of fibrin gels obtained with factor XIII treated with homocysteine was (1.47 ± 0.17) × 10^- 9 cm ², and control was (3.31 ± 0.31) × 10^- 9 cm² (n = 3; p < 0.01).Plasma incubated with high homocysteine concentrations produced fibrin clots significantly less permeable than controls in a dose dependent manner, and the results showed that fibrinogen and factor XIII were involved in that detrimental effect. These findings might explain the impaired fibrinolysis related to increased homocyteine levels and contribute to understanding the association between the amino acid and thrombosis.     

Associations between the oxytocin receptor gene (OXTR) and affect,loneliness and intelligence in normal subjects

Associations of oxytocin receptor gene (OXTR) variants and autism spectrum disorders (ASD) have been reported in earlier studies; in one of the studies associations with IQ and daily living skills were found additionally. Variations of the oxytocin receptor gene might also regulate affect, attachment and separation beyond the diagnostic borders of autism. We tested hypotheses of associations between positive and negative affects and social and emotional loneliness (285 adults), IQ (117 adolescents) and polymorphisms of the oxytocin receptor gene (OXTR rs53576, rs2254298 and rs2228485) in normal subjects. Individuals with the oxytocin OXTR rs53576 A/A genotype showed lower positive affect scores (F = 5.532, df = 1; p = 0.019). This effect was restricted to males (F = 13.098, df = 1; p = 0.00047). Haplotypes constructed with the three markers were associated with positive affect (p = 0.0012), negative affect (p < 0.0001) and emotional loneliness (p < 0.0001). Non-verbal intelligence was significantly reduced in rs53576 A/A adolescents (T = 2.247, p = 0.027). Our findings support a role for the oxytocin receptor haplotypes in the generation of affectivity, emotional loneliness and IQ.     

Genome-wide association study identifies 5q21 and 9p24.1 (<Emphasis Type="Italic">KDM4C</Emphasis>) loci associated with alcohol withdrawal symptoms

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10⁻⁴. The first best signal was rs770182 (p = 3.65 × 10⁻⁶) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10⁻⁴ (p = 7.15 × 10⁻⁶, 2.79 × 10⁻⁵ and 4.93 × 10⁻⁵, respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10⁻⁴ in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10⁻⁴ and 9.48 × 10⁻⁵, respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10⁻²) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.