APOE gene polymorphisms and susceptibility to Creutzfeldt–Jakob disease

Associations between apolipoprotein E (APOE) gene polymorphisms and Creutzfeldt–Jakob disease (CJD) have been reported, but the results from many of these studies are conflicting. To investigate the association between APOE polymorphisms and CJD risk, we performed a meta-analysis. We used odds ratios (OR) with 95% confidence intervals (CI) to assess the strength of the association. The frequency of putative risk alleles in control subjects was estimated with the Mantel-Haenszel method. Cochran’s Q statistic and the inconsistency index (I²) were used to test heterogeneity. Egger’s test and an inverted funnel plot were used to assess bias. Our study included 11 published case–control studies with APOE genotyping, involving a total of 1001 CJD patients and 1211 controls. Overall, the APOE 34 (OR 1.37, 95% CI: 1.09–1.72), and APOE 44 (OR 3.16, 95% CI: 1.37–7.26) genotypes and the APOE 4 (OR 1.41, 95% CI: 1.08–1.85) allele were associated with an increased risk of CJD, and the APOE 33 (OR 0.81, 95% CI: 0.67–0.97) genotype tended to protect against CJD. However, we did not find significant evidence supporting associations of the APOE 22 (OR 1.15, 95% CI: 0.45–2.93), APOE 23 (OR 0.84, 95% CI: 0.64–1.09), or APOE 24 (OR 1.40, 95% CI: 0.70–2.77) genotypes, nor the APOE 2 (OR 1.02, 95% CI: 0.73–1.42) or APOE 3 (OR 0.82, 95% CI: 0.65–1.02) alleles with CJD using a fixed-effects model. Our results support a genetic association between APOE polymorphisms and CJD.     

Serotonin genes and gene–gene interactions in borderline personality disorder in a matched case-control study

Lines of evidence suggest serotonin genes are susceptibility candidates in borderline personality disorder (BPD). However, few molecular genetic studies on BPD have been reported, especially an overall lack of study on epistatic interactions. We genotyped 27 polymorphisms in 7 serotonin genes in 113 Caucasian BPD patients and matched (sex, age and ethnicity) controls. Program UNPHASED was used to perform association analyses for genotypes, alleles and haplotypes with a permutation test of 10,000 simulations. The Multifactor Dimensionality Reduction analysis was used to examine gene–gene interactions in serotonin system, including three other genes (5-HTT, 5-HT2A and MAOA) that we previously reported. Genotype and allele analyses showed that BPD significantly associated with 5-HT2C and TPH2. BPD patients had high frequencies of the 5-HT2C rs6318G allele (p = 0.021) and G/G genotype (OR = 2.25); and TPH2 rs2171363T allele (p = 0.001) and T containing genotypes (OR = 3.40). The 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3A and TPH1 showed no significant association with BPD for genotype, allele and haplotype analyses. We also detected significant interactions between 5-HT2C and TPH2 (p = 0.001), and among 5-HT2C, 5-HTT, MAOA and TPH2 (p = 0.001) in BPD. Patients with 5-HT2C rs6318G/G genotype had a high frequency of TPH2 rs2171363C/T genotype compared with controls. Our study indicates ““that serotonin genes and their interactions may play a role in the susceptibility to borderline personality disorder.     

Impact of CRP gene and additional gene–smoking interaction on ischemic stroke in a Chinese Han population

Aims: To investigate the association of C-reactive protein (CRP) gene single nucleotide polymorphisms (SNPs), additional gene–gene, and gene–smoking interaction with ischemic stroke (IS) risk.

Methods: Logistic regression is performed to investigate association between SNPs within CRP gene and IS risk. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene and gene–smoking interaction, cross-validation consistency, the testing balanced accuracy and the sign test were calculated.

Results: Logistic analysis showed that three SNPs were all associated with decreased IS risk in additive and dominant models. The IS risks were lower in carriers of homozygous mutant of rs2794521 polymorphism and heterozygous of rs3093059 and rs1205 than those with wild-type homozygotes genotype, OR (95%CI) were 0.62 (0.40–0.90), 0.68 (0.50–0.96) and 0.65 (0.46–0.97), respectively. GMDR analysis suggested a significant two-locus model (P = 0.0010) involving rs2794521 and rs3093059. We also found a significant two-locus model (P = 0.0010) involving rs2794521 and smoking. Participants with rs2794521-AG or GG and rs3093059-AG or GG genotype have the lowest IS risk, compared to participants with rs2794521-AA and rs3093059-AA genotype, OR (95%CI) was 0.4 2 (0.233–0.61). In addition, non-smokers with rs2794521-AG or GG genotype have the lowest IS risk, compared to smokers with rs2794521-AA genotype, OR (95%CI) was 0.47 (0.23–0.76).

Conclusions: We found that rs2794521, rs3093059, and rs1205 were associated with decreased IS risk; we also found that gene–gene interaction between rs2794521 and rs3093059, and gene–environment interaction between rs2794521 and smoking were associated with decreased IS risk.     

Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia: A case–control study

Abstract

Objectives. Dysfunctions of the “social brain” belong to the core features of schizophrenia. The neurohormone oxytocin (OXT), mediated through its specific receptor (OXTR), is involved in the regulation of social behaviour and social cognition. Previous research has suggested a role of OXT system genes in disorders of social reciprocity. Preliminary evidence points to an association of peripheral OXT levels as well as OXT and OXTR gene polymorphisms with psychotic symptoms and treatment response in schizophrenia. This study aims to determine a possible contribution of OXT and OXTR genetic variations to schizophrenia susceptibility. Methods. Using n = 406 individuals diagnosed with schizophrenia according to DSM-IV and n = 406 healthy controls matched for age and gender in a case–control design, two single nucleotide polymorphisms (SNPs) within the OXT gene (rs2740204, rs2740210) and four SNPs within the OXTR gene (rs53576, rs237880, rs237885, rs237902) that were previously investigated in other studies were genotyped. Results. Chi²-testing suggested significant associations of OXTR SNPs rs53576(A > G) (P = 0.008) and rs237885(T > G) (P = 0.025) with a diagnosis of schizophrenia. Post-hoc ANCOVA revealed significant associations of OXTR SNPs rs53576 with general psychopathology and rs237902 with negative symptom scores in schizophrenic patients. Conclusions. Our findings support hypotheses about an involvement of oxytocinergic gene variants in schizophrenia vulnerability and warrant independent replication.     

Association study between MAO-A gene promoter VNTR polymorphisms and obsessive–compulsive disorder

A functional variant in the mono-amine oxidase-A (MAO-A) gene has been shown to affect neural function related to several mental disorders. Therefore, we would like to ascertain if MAO-A could be a candidate gene for obsessive–compulsive disorder (OCD). We genotyped 414 healthy subjects and 240 OCD patients and found no significant difference not only in allele frequencies in male patients (χ² = 0.365, DF = 1, P = 0.545, odds ratio (OR) = 1.139, confidence interval (CI) = 0.75–1.74) but also in allele frequencies (χ² = 0.698, DF = 1, P = 0.404, OR = 0.849, CI = 0.579–1.246) or genotypic frequencies (χ² = 0.933, DF = 2, P = 0.627) in female patients between OCD patients and controls. Given that this is the first investigation of this gene in OCD in a Chinese Han population, further studies are required to obtain more definitive conclusions in a larger number of subjects.     

Childhood problem behavior and parental divorce: evidence for gene–environment interaction

Objective

The importance of genetic and environmental influences on children’s behavioral and emotional problems may vary as a function of environmental exposure. We previously reported that 12-year-olds with divorced parents showed more internalizing and externalizing problems than children with married parents, and that externalizing problems in girls precede and predict later parental divorce. The aim of the current study was to investigate as to whether genetic and environmental influences on internalizing and externalizing problems were different for children from divorced versus non-divorced families.

Methods

Maternal ratings on internalizing and externalizing problems were collected with the Child Behavior Checklist in 4,592 twin pairs at ages 3 and 12?years, of whom 367 pairs had experienced a parental divorce between these ages. Variance in internalizing and externalizing problems at ages 3 and 12 was analyzed with biometric models in which additive genetic and environmental effects were allowed to depend on parental divorce and sex. A difference in the contribution of genetic and environmental influences between divorced and non-divorced groups would constitute evidence for gene–environment interaction.

Results

For both pre- and post-divorce internalizing and externalizing problems, the total variances were larger for children from divorced families, which was mainly due to higher environmental variances. As a consequence, heritabilities were lower for children from divorced families, and the relative contributions of environmental influences were higher.

Conclusions

Environmental influences become more important in explaining variation in children’s problem behaviors in the context of parental divorce.     

Lack of association between HTR4 gene polymorphisms and schizophrenia in case–control and family-based samples

Previous studies have found haplotypic association of HTR4 variants and schizophrenia. Examining case–control pairs, G–G of rs7713886 was associated with schizophrenia risk. The A–A–G–G–G–A–A rs9325104-rs1422636-rs7715569-rs6873382-rs7711800-rs10078551-rs2068190 haplotype was overrepresented in the schizophrenia cases. The associations were no longer significant after corrections for multiple comparisons. No association was found in the family sample.     

The role of gene–gene interaction in the prediction of criminal behavior

A host of research has examined the possibility that environmental risk factors might condition the influence of genes on various outcomes. Less research, however, has been aimed at exploring the possibility that genetic factors might interact to impact the emergence of human traits. Even fewer studies exist examining the interaction of genes in the prediction of behavioral outcomes. The current study expands this body of research by testing the interaction between genes involved in neural transmission. Our findings suggest that certain dopamine genes interact to increase the odds of criminogenic outcomes in a national sample of Americans.     

Examining gene–environment interactions in comorbid depressive and disruptive behavior disorders using a Bayesian approach

ObjectiveThe objective of this study was to apply a Bayesian statistical analytic approach that minimizes multiple testing problems to explore the combined effects of chronic low familial support and variants in 12 candidate genes on risk for a common and debilitating childhood mental health condition.MethodBayesian mixture modeling was used to examine gene by environment interactions among genetic variants and environmental factors (family support) associated in previous studies with the occurrence of comorbid depression and disruptive behavior disorders youth, using a sample of 255 children.ResultsOne main effect, variants in the oxytocin receptor (OXTR, rs53576) was associated with increased risk for comorbid disorders. Two significant gene × environment and one signification gene × gene interactions emerged. Variants in the nicotinic acetylcholine receptor α5 subunit (CHRNA5, rs16969968) and in the glucocorticoid receptor chaperone protein FK506 binding protein 5 (FKBP5, rs4713902) interacted with chronic low family support in association with child mental health status. One gene × gene interaction, 5-HTTLPR variant of the serotonin transporter (SERT/SLC6A4) in combination with μ opioid receptor (OPRM1, rs1799971) was associated with comorbid depression and conduct problems.ConclusionsResults indicate that Bayesian modeling is a feasible strategy for conducting behavioral genetics research. This approach, combined with an optimized genetic selection strategy (Vrieze et al., 2012), revealed genetic variants involved in stress regulation (FKBP5, SERT × OPMR), social bonding (OXTR), and nicotine responsivity (CHRNA5) in predicting comorbid status.     

Early-life stress and antidepressants modulate peripheral biomarkers in a gene–environment rat model of depression

Background

Availability of peripheral biomarkers for depression could aid diagnosis and help to predict treatment response. The objective of this work was to analyse the peripheral biomarker response in a gene–environment interaction model of depression. Genetically selected Flinders Sensitive Line (FSL) rats were subjected to maternal separation (MS), since early-life trauma is an important antecedent of depression. An open-ended approach based on a proteomic analysis of serum was combined with the evaluation of depression-associated proteins.

Methods

Rats experienced MS and chronically received escitalopram (ESC) or nortryptiline (NOR). Serum proteins were compared by two-dimensional gel electrophoresis. Corticosterone, cytokines, BDNF and C-reactive protein (CRP) were measured by immunoassays.

Results

Comparing FSL with the control Flinders Resistant Line (FRL), Apo-AI and Apo-AIV, α1-macroglobulin, glutathione peroxidase and complement-C3 were significantly modulated. Significant increases were detected in leptin, interleukin (IL) 1α and BDNF. CRP levels were significantly reduced.The impact of early-life stress was assessed by comparing FSL + MS versus FSL. Apo-E, α1-macroglobulin, complement-C3, transferrin and hemopexin were significantly modulated.The effect of stress in antidepressant response was then evaluated. In the comparison FSL + ESC + MS versus FSL + ESC, albumin, α1-macroglobulin, glutathione peroxidase and complement-C3 were modulated and significant reductions were detected in IL4, IL6, IL10, CRP and BDNF. By comparing FSL + NOR + MS versus FSL + NOR proteins like Apo-AIV, pyruvate dehydrogenase, α1-macroglobulin, transferrin and complement-C3 showed different levels.

Conclusions

Lipid metabolism and immunity proteins were differently expressed in FSL in comparison with FRL. Exposure to MS induced changes in inflammation and transport proteins which became apparent in response to antidepressant treatments. Modulated proteins could suggest biomarker studies in humans.     

Epstein–Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis

Epstein–Barr virus-induced gene 3 (EBI3) associates with p28 and p35 to form the immunomodulatory cytokines IL-27 and IL-35, respectively. Infection of EBI3 ?/? mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality that was not associated with impaired ability to control viral replication but enhanced T cell and macrophage infiltration into the CNS. IFN-γ secretion from virus-specific CD4 + and CD8 + T cells isolated from infected EBI3 ?/? mice was augmented while IL-10 expression muted in comparison to infected WT mice. These data demonstrate a regulatory role for EBI3-associated cytokines in controlling host responses following CNS viral infection.     

Gene–gene interaction between CARD8 and interleukin-6 reduces Alzheimer’s disease risk

Journal of Neurology -     

The association of CYP1A1 genetic polymorphisms and additional gene–gene interaction with ischemic stroke in the eastern Han of China

The aim of this study was to investigate the association between CYP1A1 gene polymorphism and ischaemic stroke (IS) risk, and the impact of gene–gene interaction on IS risk based on a Chinese Han case–control study. A total of 1162 subjects (612 men and 550 women), with a mean age of 63.1 ± 12.5 years old, were selected, including 580 IS patients and 582 normal controls. Logistic regression was performed to investigate association between single-nucleotide polymorphisms (SNP) and IS risk, and generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene interaction. Logistic regression analysis showed that the frequency for rs4646903 minor alleles was lower in cases than that in normal controls, and C allele of rs4646903 was 20.7 % in ischemic stroke cases and 27.1 % in controls subjects (p < 0.001). Logistic analysis showed the significant association between genotypes of variants in rs4646903 and decreased ischemic stroke risk. GMDR analysis indicated that there was a significant two-locus model (p = 0.0107) involving rs4646903 and rs1048943, indicating a potential gene–gene interaction between rs4646903 and rs1048943. Overall, the two- locus models had a cross-validation consistency of 9 of 10, and had the testing accuracy of 60.72 %. Subjects with TC or CC of rs4646903 and AG or GG of rs1048943 genotype have lowest ischemic stroke risk, compared to subjects with TT of rs4646903 and AA of rs1048943 genotype, and OR (95 % CI) was 0.63 (0.42–0.89). rs4646903 minor alleles and interaction between rs4646903 and rs1048943 were associated with decreased IS risk.     

Single gene,two diseases,and multiple clinical presentations: Biotin–thiamine-responsive basal ganglia disease

AimTo present seven new genetically confirmed cases of biotin–thiamin-responsive basal ganglia disease (BTBGD) with different clinical and brain magnetic resonance imaging (MRI) characteristics.Material and methodsGenetic variants, clinical presentations, brain MRI findings, treatment response, and prognosis of seven selected patients with BTBGD, diagnosed with SLC19A3 mutations were described.ResultsAmong seven patients diagnosed with BTBGD, two had early infantile form, four had classic childhood form, and one was asymptomatic. Four different homozygous variants were found in the SLC19A3. Two patients with early infantile form presented with encephalopathy, dystonia, and refractory seizure in the neonatal period and have different variants. Their MRI findings were similar and pathognomonic for the early infantile form. Three siblings had same variants: one presented seizure and encephalopathy at the age of 4 months, one presented seizure at 14 years, and another was asymptomatic at 20 years. Only one of them had normal MRI findings, and the others MRI findings were similar and suggestive of the classic form. Other two siblings; one of them presented with developmental delay, seizure, and dystonia at 18 months and the other presented with subacute encephalopathy and ataxia at 20 months. Their MRI findings were also similar and suggestive of the classic form.ConclusionBTBGD may present with dissimilar clinical characteristics or remain asymptomatic for a long time period even in a family or patients with same variants. Brain MRI patterns may be important for the early diagnosis of BTBGD that would save children’s lives.     

Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen–amyloid beta complex formation during hyperhomocysteinemia

Increased blood level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) accompanies many cognitive disorders including Alzheimer''s disease. We hypothesized that HHcy-enhanced cerebrovascular permeability occurs via activation of matrix metalloproteinase-9 (MMP9) and leads to an increased formation of fibrinogen–β-amyloid (Fg–Aβ) complex. Cerebrovascular permeability changes were assessed in C57BL/6J (wild type, WT), cystathionine-β-synthase heterozygote (Cbs+/−, a genetic model of HHcy), MMP9 gene knockout (Mmp9−/−), and Cbs and Mmp9 double knockout (Cbs+/−/Mmp9−/−) mice using a dual-tracer probing method. Expression of vascular endothelial cadherin (VE-cadherin) and Fg–Aβ complex formation was assessed in mouse brain cryosections by immunohistochemistry. Short-term memory of mice was assessed with a novel object recognition test. The cerebrovascular permeability in Cbs+/− mice was increased via mainly the paracellular transport pathway. VE-cadherin expression was the lowest and Fg–Aβ complex formation was the highest along with the diminished short-term memory in Cbs+/− mice. These effects of HHcy were ameliorated in Cbs+/−/Mmp9−/− mice. Thus, HHcy causes activation of MMP9 increasing cerebrovascular permeability by downregulation of VE-cadherin resulting in an enhanced formation of Fg–Aβ complex that can be associated with loss of memory. These data may lead to the identification of new targets for therapeutic intervention that can modulate HHcy-induced cerebrovascular permeability and resultant pathologies.     

Late-onset Charcot–Marie–Tooth disease 4F caused by periaxin gene mutation

We identified the main features of Charcot–Marie–Tooth (CMT) disease, type 4F, caused by a periaxin gene (PRX) mutation in Japanese patients. Periaxin is known as one of the key myelination molecules, forming tight junction between myelin loop and axon. We collected 427 DNA samples from individuals with CMT or CMT-related neuropathy, negative for PMP22 duplication. We investigated PRX mutations using a purpose-built resequencing array screen during the period 2006–2012. We detected two types of PRX mutations in three patients; one patient showed a novel homozygous p.D651N mutation and the other two showed homozygous p.R1070X mutation. All PRX mutations reported so far have been of nonsense or frameshift type. In this study, we found homozygous missense mutation p.D651N. Aspartate 651 is located in a repeat domain; its position might indicate an important function. PRX mutations usually lead to early-onset, autosomal-recessive demyelinating CMT neuropathy 4F (CMT4F) or Dejerine–Sottas disease; their clinical phenotypes are severe. In our three patients, the onset of the disease was at the age of 27?years or later, and their clinical phenotypes were milder compared with those reported in previous studies. We showed a variation of clinical phenotypes for CMT4F caused by a novel, nonsense PRX mutation.     

Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene–gene interactions using complementary case–control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene–gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between ∼61% and 85% accuracy. These results suggest that significant epistasis, or gene–gene interactions, may exist even in the absence of statistically significant individual main effects.Alison A. Motsinger and David Brassat contributed equally to this work.