Association of APOE gene with longitudinal changes of CSF amyloid beta and tau levels in Alzheimer's disease: racial differences.

BACKGROUND: The Apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease (AD). However, no investigation has focused on racial differences in the longitudinal effect of APOE genotypes on CSF amyloid beta (Aß42) and tau levels in AD. METHODS: This study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 222 participants with AD, 264 with cognitive normal (CN), and 692 with mild cognitive impairment (MCI) at baseline and two years follow-up. We used a linear mixed model to investigate the effect of APOE-ε4-genotypes on longitudinal changes in the amyloid beta and tau levels. RESULTS: Individuals with 1 or 2 APOE ε4 alleles revealed significantly higher t-Tau and p-Tau, but lower amyloid beta Aß42 compared with individuals without APOE ε4 alleles. Significantly higher levels of log-t-Tau, log-p-Tau, and low levels of log-Aß42 were observed in the subjects with older age, being female, and the two diagnostic groups (AD and MCI). The higher p-Tau and Aß42 values are associated with poor Mini-Mental State Examination (MMSE) performance. Non-Hispanic Africa American (AA) and Hispanic participants were associated with decreased log-t-Tau levels (ß = - 0.154, p = 0.0112; ß = - 0.207, and p = 0.0016, respectively) as compared to those observed in Whites. Furthermore, Hispanic participants were associated with a decreased log-p-Tau level (ß = - 0.224, p = 0.0023) compared to those observed in Whites. There were no differences in Aß42 level for non-Hispanic AA and Hispanic participants compared with White participants. CONCLUSION: Our study, for the first time, showed that the APOE ε4 allele was associated with these biomarkers, however with differing degrees among racial groups.

Racial differences in the effect of APOE-ε4 genotypes on trail making test B in Alzheimer's disease: A longitudinal study.

OBJECTIVES: The trail making test part B (TMT-B) evaluates executive functions, memory, and sensorimotor functions. No previous study was found to examine the longitudinal effect of APOE-ε4 genotypes on the TMT-B scores in Alzheimer's disease (AD) across racial groups. METHODS: This study used the data from Alzheimer's Disease Neuroimaging Initiative (ADNI): 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) at baseline and follow-up of four years. The multivariable linear mixed model was used to investigate the effect of APOE-ε4 genotypes on changes in TMT-B scores. RESULTS: Compared with Whites, African Americans (AA) and Hispanics had higher TMT-B scores (poor cognitive function). Furthermore, Whites subjects with 1 or 2 APOE-ε4 alleles had significantly higher TMT-B scores compared with individuals without APOE-ε4 allele at baseline and four follow-up visits; however, no differences in TMT-B were found between APOE-ε4 alleles in the Hispanic and AA groups. No APOE-ε4 by visit interactions was found for 3 racial groups. Stratified by AD diagnosis, the APOE-ε4 allele was associated with TMT-B scores only in the MCI group, while there were significant interactions for visit by education, APOE-ε4 allele, and the Mini Mental State Examination (MMSE) score in the MCI group. In addition, TMT-B was significantly correlated with the MMSE, AD Assessment Scale-cognitive subscale 13 (ADAS13), tTau, pTau, Aß42, and hippocampus. CONCLUSIONS: APOE-ɛ4 allele is associated with TMT-B scores in Whites subjects, but not in the Hispanic and AA groups. APOE-ε4 showed interaction with visit in the MCI group.

APOE Gene Associated with Dementia-Related Traits, Depression, and Anxiety in the Hispanic Population.

Alzheimer's disease (AD), a main cause of dementia, is commonly seen in aging populations with a strong genetic component. AD is one of the most common neurodegenerative disorders; it is a genetically and clinically heterogeneous disease. Specific demographic factors and genetic variants have been identified in non-Hispanic populations; however, limited studies have observed the Hispanic population. Therefore, we focused on investigating a known gene, APOE, associated with AD-related phenotypes and two psychiatric diseases (depression and anxiety) within the U.S. Hispanic population in our current study. A total of 1382 subjects were studied based on data collected from the Texas Alzheimer's Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires regarding demographics, medical history, and blood/saliva samples were collected. We genotyped the APOE gene. The current findings indicated that APOE-ε4 was associated with not only AD (p < 0.0001) but also with anxiety (p < 0.0001) and depression (p = 0.0004). However, APOE-ε3 was associated with depression (p = 0.002) in the Hispanic population. We provide additional evidence in which APOE-ε4 increased the risk for AD in Hispanics. For the first time, APOE alleles show increased risks for anxiety and depression in Hispanics. Further research is warranted to confirm the current findings.

Altered DNA methylation of CYP2E1 gene in schizophrenia patients with tardive dyskinesia.

BACKGROUND: About 20-30% of patients with schizophrenia develop tardive dyskinesia (TD). Oxidative stress is one potential causes of TD. CYP2E1 is considered as an oxidative stress-related gene, however, no study has been reported on the DNA methylation levels of the CYP2E1 in schizophrenia or TD. METHODS: A total of 35 schizophrenia patients with TD, 35 schizophrenia patients without TD (NTD), and 35 health controls (HCs) were collected in Beijing, China. DNA was extracted from peripheral blood samples. The promoter methylation levels of CYP2E1 were detected using pyrosequencing. The generalized linear model (GLM) was used to examine the methylation levels of three CpG sites among three diagnostic groups (TD vs. NTD vs. HC). RESULTS: The average methylation levels were 8.8 ± 10.0, 14.5 ± 11.9 and 15.1 ± 11.3 in TD, NTD and HC groups, respectively. The F-test in GLM revealed overall differences in the average of methylation levels of three CpG sites among three diagnostic groups (p = 0.0227) and in the third CpG site (p = 0.0026). Furthermore, the TD group had lower average methylation levels than HC and NTD groups (p = 0.0115 and 0.0268, respectively). Specifically, TD group showed lower methylation levels in the third CpG site than HC and NTD groups (p = 0.0012 and 0.0072, respectively). Additionally, associations of the methylation levels with clinical features in the TD group were observed using Spearman correlation analysis. CONCLUSION: This study provides the first evidence of DNA methylation levels in the promoter of CYP2E1 gene associated with schizophrenia and TD. The abnormal DNA methylation might serve as a potential mechanism for TD.

Gender differences in the associations of multiple psychiatric and chronic conditions with major depressive disorder among patients with opioid use disorder.

PURPOSE: The study examined the associations of multiple psychiatric and chronic conditions with the self-reported history of major depressive disorder (MDD) among patients with opioid use disorder (OUD) and tested whether the associations differed by gender. METHODS: We conducted a secondary data analysis of baseline data from a clinical trial including 1,646 participants with OUD, of which 465 had MDD. A variable cluster analysis was used to classify chronic medical and psychiatric conditions. Multivariable logistic regression analyses were used to estimate their associations with MDD in subjects with OUD. RESULTS: Nine variables were divided into three clusters: cluster 1 included heart condition, hypertension, and liver problems; cluster 2 included gastrointestinal (GI) problems and head injury, and cluster 3 included anxiety disorder, bipolar disorder, and schizophrenia. The overall prevalence of MDD in participants with OUD was 28.3% (22.8% for males and 39.5% for females). Gender, anxiety disorder, schizophrenia, liver problems, heart condition, GI problems, and head injury were significantly associated with MDD. Gender-stratified analyses showed that bipolar disorder, liver problems and individuals with one chronic condition were associated with MDD only in males, whereas heart condition, hypertension, and GI problems were associated with MDD only in females. In addition, anxiety disorder, head injury, individuals with one or more than two psychiatric conditions, and individuals with more than two chronic conditions were associated with MDD regardless of gender. CONCLUSIONS: Treatment plans in patients with OUD should not only address MDD but also co-morbid psychiatric and chronic medical conditions that occur with MDD.

Polysubstance Use, Mood Disorders, and Chronic Conditions With Anxiety in Opioid Patients.

This study examined the associations of polysubstance use, mood disorders, and chronic conditions with the history of anxiety disorder among patients with opioid use disorder (OUD). We performed a secondary analysis of the baseline data from a clinical trial including 1,645 individuals with OUD, of which 513 had anxiety disorder. Substance use disorders (SUDs) included alcohol, amphetamines, cannabis, cocaine, and sedative use disorders. Mood disorders included major depressive disorder (MDD) and bipolar disorder (BD). Chronic conditions were allergies, gastrointestinal problem(s), skin problem(s), and hypertension. Sedative use disorder, MDD, BD, skin problems, and hypertension were significantly associated with anxiety disorder (p < 0.05). Additionally, more than two SUDs, two mood disorders, and more than two chronic conditions were significantly associated with anxiety disorder (p < 0.05). These findings highlight the comorbid mental health and physical health problems in individuals with OUD, as well as the need for integrated multidisciplinary treatment plans.

Gender differences in the associations of early onset poly tobacco and drug use prior to age 18 with the prevalence of adult bronchitis in the United States.

PURPOSE: We investigated the associations of early onset polysubstance use prior to age 18 with the prevalence of bronchitis among U.S. adults and tested whether the associations differ by gender. METHODS: A total of 77,950 adults, of them 2,653 with bronchitis in the past year, were from the combined 2013 and 2014 National Survey on Drug Use and Health data. The variable cluster analysis was used to classify nine variables about substance use prior to age 18 (cigarettes, cigars, smokeless tobacco, marijuana, cocaine, heroin, methamphetamines, ecstasy, and phencyclidine). Weighted multivariate logistic regression analysis (MLR) was used to examine the associations with bronchitis. RESULTS: Nine variables were divided into two clusters: early onset poly tobacco use (three tobacco use variables) and early onset poly drug use (six drug use variables). The overall prevalence of bronchitis was 3.8% (5.1% for females and 2.3% for males). MLR analysis showed that being female, elderly (ages 65 and above), obese, and early onset poly tobacco use were associated with increased odds of bronchitis (p < 0.05). Gender-stratified analyses showed that early-onset poly tobacco use was significantly associated with bronchitis only in males, whereas early onset poly drug use was associated with bronchitis only in females. Moreover, obesity and tobacco use in the past year revealed associations with bronchitis regardless of gender. CONCLUSIONS: Obesity, early onset poly tobacco use prior to age 18, and tobacco use in the past year were positively associated with bronchitis; furthermore, the associations of early onset polysubstance use with bronchitis differed by gender, which indicated that gender differences should be considered in developing effective prevention strategies.

Polymorphisms Within RYR3 Gene Are Associated With Risk and Age at Onset of Hypertension, Diabetes, and Alzheimer's Disease.

BACKGROUND: Hypertension affects 33% of Americans while type 2 diabetes and Alzheimer's disease (AD) affect 10% of Americans, respectively. Ryanodine receptor 3 gene (RYR3) codes for the RYR which functions to release stored endoplasmic reticulum calcium ions (Ca2+) to increase intracellular Ca2+ concentration. Increasing studies demonstrate that altered levels of intracellular Ca2+ affect cardiac contraction, insulin secretion, and neurodegeneration. In this study, we investigated associations of the RYR3 genetic variants with hypertension, AD, and diabetes. METHODS: Family data sets were used to explore association of RYR3 polymorphisms with risk and age at onset (AAO) of hypertension, diabetes, and AD. RESULTS: Family-based association tests using generalized estimating equations (FBAT-GEE) showed several unique or shared disease-1 associated variants in the RYR3 gene. Three single nuclear polymorphisms (SNPs; rs2033610, rs2596164, and rs2278317) are significantly associated with risk for hypertension, diabetes, and AD. Two SNPs (rs4780174 and rs7498093) are significantly associated with AAO of the 3 diseases. CONCLUSIONS: RYR3 variants are associated with hypertension, diabetes, and AD. Replication of these results of this gene in these 3 complex traits may help to better understand the genetic basis of calcium-signaling gene, RYR3 in association with risk and AAO of these diseases.

Discriminating between positional and non-positional obstructive sleep apnea using some clinical characteristics.

PURPOSE: The primary objective of this paper was to identify significant factors associated with positional Obstructive Sleep Apnea (POSA) and to provide a clinical tool for discriminating non positional from POSA. Secondary objectives were about estimating the prevalence of POSA, comparing the polysomnographic variables across POSA and non-POSA patients. METHODS: This was a cross sectional study on 278 patients who completed an overnight sleep study for OSA assessment. Patients were aged over 18 years, without central sleep apnea or narcolepsy and slept no less than 20 min in a non-supine position. POSA was defined as a total apnea/hypopnea index (AHI) ≥5 and a ratio supine AHI/non-supine AHI ≥2. The binary logistic regression was used for modeling the likelihood for OSA patient to be positional, and the LASSO method was used for selecting the optimal set of clinical characteristics associated with POSA. RESULTS: Overall, 53% of patients had POSA. These patients were younger (p = 0.005), had lower BMI (p < 0.0001), lower prevalence of hypertension (p = 0.006), lower Berlin (p = 0.01), and lower STOP (p = 0.001) scores compared to non-POSA patients. Neck and waist circumference were higher in non-POSA (p = 0.005, p = 0.009, respectively) patients. Age, BMI, DBP, Mallampati, and Berlin scores were found to be the best clinical characteristics associated with POSA with an area under the ROC curve (AUC) of 0.71 (95% CI [0.63, 0.78]). CONCLUSIONS: Half of patients referred for the sleep study had POSA. Age, BMI, DBP, Mallampati, and Berlin scores, put together, were shown to act as good clinical characteristics to discriminate between POSA and non-POSA patients.

Novel Somatic Copy Number Alteration Identified for Cervical Cancer in the Mexican American Population.

Cervical cancer affects millions of Americans, but the rate for cervical cancer in the Mexican American is approximately twice that for non-Mexican Americans. The etiologies of cervical cancer are still not fully understood. A number of somatic mutations, including several copy number alterations (CNAs), have been identified in the pathogenesis of cervical carcinomas in non-Mexican Americans. Thus, the purpose of this study was to investigate CNAs in association with cervical cancer in the Mexican American population. We conducted a pilot study of genome-wide CNA analysis using 2.5 million markers in four diagnostic groups: reference (n = 125), low grade dysplasia (cervical intraepithelial neoplasia (CIN)-I, n = 4), high grade dysplasia (CIN-II and -III, n = 5) and invasive carcinoma (squamous cell carcinoma (SCC), n = 5) followed by data analyses using Partek. We observed a statistically-significant difference of CNA burden between case and reference groups of different sizes (>100 kb, 10-100 kb and 1-10 kb) of CNAs that included deletions and amplifications, e.g., a statistically-significant difference of >100 kb deletions was observed between the reference (6.6%) and pre-cancer and cancer (91.3%) groups. Recurrent aberrations of 98 CNA regions were also identified in cases only. However, none of the CNAs have an impact on cancer progression. A total of 32 CNA regions identified contained tumor suppressor genes and oncogenes. Moreover, the pathway analysis revealed endometrial cancer and estrogen signaling pathways associated with this cancer (p < 0.05) using Kyoto Encyclopedia of Genes and Genomes (KEGG). This is the first report of CNAs identified for cervical cancer in the U.S. Latino population using high density markers. We are aware of the small sample size in the study. Thus, additional studies with a larger sample are needed to confirm the current findings.

Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p < 2 × 10(-3). The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10(-4)). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p < 0.05). Furthermore, Kaplan-Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.

NRG3 gene is associated with the risk and age at onset of Alzheimer disease.

The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10(-5)). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.

Congenital heart block maternal sera autoantibodies target an extracellular epitope on the α1G T-type calcium channel in human fetal hearts.

BACKGROUND: Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.

Genetic association analysis of ITGB3 polymorphisms with age at onset of schizophrenia.

Schizophrenia (SCZ) is a debilitating disorder with a prevalence of approximately 1 % worldwide. SCZ is known to have a high degree of genetic and clinical heterogeneity and is a major health problem worldwide. The integrin-ß 3 subunit gene (ITGB3) gene at 17q21.32 has been implicated in psychiatric disorders. We therefore hypothesized that ITGB3 gene polymorphisms might also play a role in SCZ and age at onset (AAO) of SCZ. We investigated the genetic associations of 23 single-nucleotide polymorphisms (SNPs) of the ITGB3 gene with AAO in SCZ in two Caucasian samples (2,166 cases and 2,525 controls) using linear regression analysis and meta-analysis. We observed four ITGB3-SNPs associated with AAO in SCZ in a non-Genetic Association Information Network (GAIN) sample (p < 10(-3)). Three of these four SNPs were replicated in the GAIN sample. The SNP rs16941771 was most significantly associated with AAO (p = 7.47 × 10(-5)). Meta-analysis showed that 6 of 23 SNPs were associated with AAO. The haplotype analysis also supports the association of ITGB3 with AAO. Three disease-associated SNPs were located at species-conserved regions, indicating functional importance. This is the first report which shows that ITGB3 variants are associated with AAO in SCZ, providing direct evidence of the use of AAO as an intermediate phenotype to dissect the complex genetics of SCZ.

BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies.

Schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p<5×10(-5). Especially we detected five SNPs in the first two genes/loci strongly associated with negative symptoms of schizophrenia (P(meta-analysis)<6.22×10(-6)), which included three SNPs in the BCL9 gene: rs583583 showed the strongest association at a P(meta-analysis) of 6.00×10(-7) and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 ×10(-6)). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes.

Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene × gender interaction.

BACKGROUND: Previous reports have suggested that there may be gene × gender interaction for bipolar disorder (BD)-associated genes/loci at 22q11-13. This study aimed to investigate the associations of SEZ6L genetic variants with bipolar disorder I (BD-I) and to examine gender-specific genetic associations. METHODS: 605 BD-I Caucasian cases and 1034 controls were selected from the publicly available data of the Whole Genome Association Study of BD. To increase power, an additional 362 Caucasian controls were added to this study from the Genome-Wide Association Study of Schizophrenia. In total, 605 BD-I cases and 1396 controls (934 males and 1067 females) were available for genetic association analysis of 118 SNPs within the SEZ6L gene using PLINK software. RESULTS: 16 SNPs showed significant gene x gender interactions influencing BD-I (P<0.01). In addition, significant differences in the distribution of the alleles for these 16 SNPs were observed between the female BD-I patients and healthy controls (P<0.015) but no significant associations were found for the male sample (P>0.05). The SNP rs4822691 showed the strongest association with BD-I in the female sample (P=2.18 × 10(-4)) and the strongest gene × gender interaction in influencing BD-I (P=9.16 × 10(-5)). LIMITATIONS: The findings of this study need to be replicated in independent samples. CONCLUSIONS: This is the first demonstration that genetic variants in the SEZ6L gene are associated with BD-I in female patients and provides additional compelling evidence for genetic variation at 22q11-13 that influences BD-I risk. The present findings highlight the gene x gender interactions modifying BD-I susceptibility.

Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production.

Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-D-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-agonist glycine or NMDA into the dorsal vagal complex (DVC), targeting the nucleus of the solitary tract, lowered glucose production in vivo. Direct infusion of the NMDA receptor blocker MK-801 into the DVC negated the metabolic effect of glycine. To evaluate whether NR1 subunit of the NMDA receptor mediates the effect of glycine, NR1 in the DVC was inhibited by DVC NR1 antagonist 7-chlorokynurenic acid or DVC shRNA-NR1. Pharmacological and molecular inhibition of DVC NR1 negated the metabolic effect of glycine. To evaluate whether the NMDA receptors mediate the effects of NR2 agonist NMDA, DVC NMDA receptors were inhibited by antagonist D-2-amino-5-phosphonovaleric acid (D-APV). DVC D-APV fully negated the ability of DVC NMDA to lower glucose production. Finally, hepatic vagotomy negated the DVC glycine ability to lower glucose production. These findings demonstrate that activation of NR1 and NR2 subunits of the NMDA receptors in the DVC is sufficient to trigger a brain-liver axis to lower glucose production, and suggest that DVC NMDA receptors serve as a therapeutic target for diabetes and obesity.

POU homeodomain protein Oct-1 functions as a sensor for cyclic AMP.

Cyclic AMP is a fundamentally important second messenger for numerous peptide hormones and neurotransmitters that control gene expression, cell proliferation, and metabolic homeostasis. Here we show that cAMP works with the POU homeodomain protein Oct-1 to regulate gene expression in pancreatic and intestinal endocrine cells. This ubiquitously expressed transcription factor is known as a stress sensor. We found that it also functions as a repressor of Cdx-2, a proglucagon gene activator. Through a mechanism that involves the activation of exchange protein activated by cyclic AMP, elevation of cAMP leads to enhanced phosphorylation and nuclear exclusion of Oct-1 and reduced interactions between Oct-1 or nuclear co-repressors and the Cdx-2 gene promoter, detected by chromatin immunoprecipitation. In rat primary pancreatic islet cells, cAMP elevation also reduces nuclear Oct-1 content, which causes increased proglucagon and proinsulin mRNA expression. Our study therefore identifies a novel mechanism by which cAMP regulates hormone-gene expression and suggests that ubiquitously expressed Oct-1 may play a role in metabolic homeostasis by functioning as a sensor for cAMP.