We investigated the role of a single nucleotide polymorphism rs3764030 (G>A) within the human GRIN2B promoter in mental processing speed in healthy, cognitively intact, older adults. In vitro DNA-binding and reporter gene assays of different allele combinations in transfected cells showed that the A allele was a gain-of-function variant associated with increasing GRIN2B mRNA levels. We tested the hypothesis that individuals with A allele will have better memory performance (i.e. faster reaction times) in older age. Twenty-eight older adults (ages 65-86) from a well-characterized longitudinal cohort were recruited and performed a modified delayed match-to-sample task. The rs3764030 polymorphism was genotyped and participants were grouped based on the presence of the A allele into GG and AA/AG. Carriers of the A allele maintained their speed of memory retrieval over age compared to GG carriers (p = 0.026 slope of the regression line between AA and AG versus GG groups). To validate the results, 12 older adults from the same cohort participated in a different version of the short-term memory task. Reaction times were significantly slower with age in older adults with G allele (p < 0.001). These findings support a role for rs3764030 in maintaining faster mental processing speed over aging.

OBJECTIVE

Pathological alterations of glutamatergic systems were observed in neurodegenerative and psychiatric disorders. There is some evidence that this system may be involved in the genetic vulnerability to suicide. The aim of the present study was to analyze possible relationship between the GRIN2B polymorphism and suicidal behavior. We hypothesized that this genetic factor may be associated with suicide attempts in alcohol-dependent patients and with death by suicide.

METHODS

To analyze the relationship between GRIN2B and suicide attempts, the selected rs2268115 polymorphism was genotyped in a sample of 345 alcohol-dependent individuals stratified by the history of suicide attempts. The second part of the study concerning suicide was based on a sample of 510 suicide victims and 450 controls.

RESULTS

The frequency of rs2268115 G allele among alcohol-dependent patients with the history of suicide attempts was significantly higher than among non-suicidal alcohol-dependent individuals (OR = 1.45, p = .033). This association was more significant when analyzing alcohol-dependent patients only without co-occurring drug dependence (OR = 1.62, p = .021). The analyzed GRIN2B polymorphism was associated with a twofold increase in odds of a suicide attempt (OR = 2.01, p = .004). No relationships between rs2268115 and death by suicide were identified.

CONCLUSIONS

Our results suggest that glutamatergic system influence susceptibility to suicide attempts in alcohol-dependent individuals. Suicidal behavior and alcohol dependence may share a common etiology related to the glutamatergic system.

CONCLUSIONS

The major contribution of the present study is a novel finding of the possible association between GRIN2B rs2268115 polymorphism and suicide attempts in alcohol-dependent individuals. (Am J Addict 2017;26:595-601).

OBJECTIVE

To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis.

RESULTS

Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1.22-3.64], 1.7x risk (95% CI 1.13-2.59), and 2.15x risk (95% CI 1.3-3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1-4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120 bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03-0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results.

CONCLUSIONS

Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts.

We reported previously that monoamine oxidase (MAO) A knockout (KO) mice show increased serotonin (5-hydroxytryptamine, 5-HT) levels and autistic-like behaviors characterized by repetitive behaviors, and anti-social behaviors. We showed that administration of the serotonin synthesis inhibitor para-chlorophenylalanine (pCPA) from post-natal day 1 (P1) through 7 (P7) in MAO A KO mice reduced the serotonin level to normal and reverses the repetitive behavior. These results suggested that the altered gene expression at P1 and P7 may be important for the autistic-like behaviors seen in MAO A KO mice and was studied here. In this study, Affymetrix mRNA array data for P1 and P7 MAO A KO mice were analyzed using Partek Genomics Suite and Ingenuity Pathways Analysis to identify genes differentially expressed versus wild-type and assess their functions and relationships. The number of significant differentially expressed genes (DEGs) varied with age: P1 (664) and P7 (3307) [false discovery rate (FDR) <0.05, fold-change (FC) >1.5 for autism-linked genes and >2.0 for functionally categorized genes]. Eight autism-linked genes were differentially expressed in P1 (upregulated: NLGN3, SLC6A2; down-regulated: HTR2C, MET, ADSL, MECP2, ALDH5A1, GRIN3B) while four autism-linked genes were differentially expressed at P7 (upregulated: HTR2B; downregulated: GRIN2D, GRIN2B, CHRNA4). Many other genes involved in neurodevelopment, apoptosis, neurotransmission, and cognitive function were differentially expressed at P7 in MAO A KO mice. This result suggests that modulation of these genes by the increased serotonin may lead to neurodevelopmental alteration in MAO A KO mice and results in autistic-like behaviors.

OBJECTIVE

To search for genetic mechanisms of facial emotion recognition (FER) impairment, one of the features of schizophrenia that affects social adaptation of patients. Based on the view implicating the interplay between dopaminergic and glutamatergic systems into the pathogenesis of schizophrenia, authors explored the interaction effects of the C366G polymorphism in the GRIN2B gene encoding NMDA receptor subunit NR2B with ANKK1/DRD2 Taq1A and 48-VNTR DRD4 polymorphisms on FER.

METHODS

GRIN2B -DRD2 interaction effects were studied in a sample of 237 patients and 235 healthy controls, GRIN2B - DRD4 in 268 patients and 208 controls.

CONCLUSIONS

Both effects were significant in combined samples of patients and controls (GRIN2B X DRD2, F=4.12, p=0.043; GRIN2B X DRD4, F=6.43, p=0.012). Further analysis confirmed the interaction effect of GRIN2B and DRD2 polymorphisms on FER in patients with schizophrenia. In patients with a less efficient allele of the DRD2 in the absence of the minor allele of the GRIN2B C366G polymorphism, the results were close to normal values while patients with minor alleles of both polymorphisms showed the worst results. This finding is in line with the conceptions on a possible role of NMDA-receptor hypofunction and D2-mediated regulation of NMDA-receptor activity in FER impairments in schizophrenia.

Caffeine is one of the most extensively consumed stimulants in the world and has been suggested to induce wakefulness by antagonizing the function of the adenosine A2A receptor. Therefore, we investigated the effects of chronic caffeine consumption on learning and memory in the REM sleep-deprived rats.Male Wistar rats (n = 50), were randomly assigned into 5 groups: Control (C), Caffeine (Cf), Pedestal Control (PC), Sleep Deprivation (SD), Sleep Deprivation and Caffeine (SD + Cf). Sleep deprivation procedure was applied as the flower-pot technique. SD and SD + Cf groups were deprived for 18 hours in a day for 21 days. Caffeine was administered daily in drinking water (0.3 g⁄L) for 5 weeks. For evaluated learning and memory function, Morris Water Maze Test (MWM) was used. Fluidigm Access Array was used for Grin2a, Grin2b, BDNF, cdk5/cdk5r1, CaMKIIa genes expression in the hippocampus. Distance moved and escape latency were decreased through trial days (p&lt;0.05). However, there is no significant difference between groups for time spent in targeted quadrant during probe test for memory performance. Grin2a up-regulation was found in Cf and SD+Cf (p&lt;0.05), and cdk5r1 increased in Cf and PC control (p&lt;0.05). Also, BDNF up-regulation was found in PC group. Grin2b, Cdk5, CaMKIIa expression levels were not changed significantly. We showed chronic caffeine altered some of the hippocampal genes without changing learning and memory in REM sleep deprived rats. Chronic consumption of caffeine caused up-regulation in Grin2a that subunit of NMDA receptor. We supposed that chronic caffeine consumption maintained arousal without affecting learning and memory performance.

Maternal consumption of a high-fat diet (HFD) during pregnancy increases the risk of behavioral problems. Folate plays an important role in neuroplasticity and the preservation of neuronal integrity. This study aims at determining the influence of diets supplemented with folate on offspring behavior, and the mechanisms involved.

Female mice were fed a control diet, an HFD, control diet supplemented with folate, or an HFD supplemented with folate for 5 weeks before mating. Open field task and elevated plus maze are used to evaluate the offspring behaviors. Results showed that offspring cognitive performance and anxiety-related behaviors, including those related to open field exploration and elevated plus maze, were significantly improved when dams were treated with folate in pregnancy. Moreover, the maternal folate supplement decreased BDNF and Grin2b methylation and upregulated their expressions in the brain of offspring, which were associated with decreasing the expression of DNA methyltransferases compared with those dams were treated only HFD in pregnancy.

Maternal folate supplementation ameliorates behavior disorders induced by prenatal high-fat diet. The beneficial effects were associated with methylation and expression alteration of BDNF and Grin2b genes.

OBJECTIVE

The N-methyl-D-aspartate receptor subunit 2B (GluN2B) is involved in regulation of anxiety and depression and nervous activity in the brain. Single nucleotide polymorphisms of the GluN2B gene (GRIN2B) are associated with human mental function and behaviour. We investigated whether four GRIN2B polymorphisms (rs7301328, rs1806201, rs1805247, and rs1805502) affect characterisation of personality traits.

METHODS

In 248 young people, GRIN2B polymorphisms were analysed, and personality traits were assessed using the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) and State-Trait Anxiety Inventory (STAI).

RESULTS

There was no main effect of the GRIN2B polymorphisms on the NEO-FFI and STAI dimension scores. Interaction between polymorphism and sex was found in rs1805247 (p = 0.034) and rs1805502 (p = 0.040) in terms of the conscientiousness score of the NEO-FFI. However, post hoc simple main effect analysis showed no significant effect. The preliminary haplotype analysis indicated that haplotype CTT (rs1806201-rs1805247-rs1805502) in the haplotype block was associated with the extraversion score of the NEO-FFI in female participants (p = 0.044), but the significance was lost on correction for multiple testing.

CONCLUSIONS

There was no significant association between selected GRIN2B polymorphisms and personality traits, but this may be due to low statistical power. Further studies involving a larger study population are needed to clarify this.

Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system that affects primarily distal respiratory pathways and lung parenchyma. Smoking tobacco is a major risk factor for COPD. The relationship of HTR4 (rs3995090), HTR2A (rs6313), GRIK5 (rs8099939), GRIN2B (rs2268132), and CHRNB4 (rs1948) gene polymorphisms and COPD, as well as the contribution of these polymorphisms to the variations in quantitative characteristics that describe respiratory function, smoking behavior, and nicotine dependence was assessed in an ethnically homogeneous Tatar population. The polymorphisms of HTR2A (rs6313) (P = 0.026, OR = 1.42 for the CC genotype) and GRIN2B (rs2268132) (P = 0.0001, OR = 2.39 for the TT genotype) were significantly associated with increased risk of COPD. The AA genotype of GRIK5 (rs8099939) had a protective effect (P = 0.02, OR = 0.61). Importantly, the HTR2A (rs6313), GRIN2B (rs2268132), and GRIK5 (rs8099939) polymorphisms were only associated with COPD in smokers. Smoking index (pack-years) was significantly higher in carriers of the GRIK5 genotype AC (rs8099939) (P = 0.0027). The TT genotype of GRIN2B (rs2268132) was associated with COPD in subjects with high nicotine dependence according to the Fagerstrõm test (P = 0.002, OR = 2.98). The TT genotype of HTR2A (rs6313) was associated with a reduced risk of the disease in the group with moderate nicotine dependence (P = 0.02, OR = 0.22). The CC genotype of HTR2A (rs6313) and the TT genotype of GRIN2B (rs2268132) were associated with higher levels of nicotine dependence according to the Fagerstrõm test (P = 0.0011 and P = 0.037). Our results may provide insight into potential molecular mechanisms that involve the glutamate (GRIK5, GRIN2B) and serotonin (HTR2A) receptor genes in the pathogenesis of COPD.

Accruing evidence supports the hypothesis that memory deficits in early Alzheimer Disease (AD) might be due to synaptic failure caused by accumulation of intracellular amyloid beta (Aβ) oligomers, then secreted to the extracellular media. Transgenic mouse AD models provide valuable information on AD pathology. However, the failure to translate these findings to humans calls for models that better recapitulate the human pathology. McGill-R-Thy1-APP transgenic (Tg) rat expresses the human amyloid precursor protein (APP751) with the Swedish and Indiana mutations (of familial AD), leading to an AD-like slow-progressing brain amyloid pathology. Therefore, it offers a unique opportunity to investigate learning and memory abilities at early stages of AD, when Aβ accumulation is restricted to the intracellular compartment, prior to plaque deposition. Our goal was to further investigate early deficits in memory, particularly long-term memory in McGill-R-Thy1-APP heterozygous (Tg+/-) rats. Short-term- and long-term habituation to an open field were preserved in 3-, 4-, and 6-month-old (Tg+/-). However, long-term memory of inhibitory avoidance to a foot-shock, novel object-recognition and social approaching behavior were seriously impaired in 4-month-old (Tg+/-) male rats, suggesting that they are unable to either consolidate and/or evoke such associative and discriminative memories with aversive, emotional and spatial components. The long-term memory deficits were accompanied by increased transcript levels of genes relevant to synaptic plasticity, learning and memory processing in the hippocampus, such as Grin2b, Dlg4, Camk2b, and Syn1. Our findings indicate that in addition to the previously well-documented deficits in learning and memory, McGill-R-Thy1-APP rats display particular long-term-memory deficits and deep social behavior alterations at pre-plaque early stages of the pathology. This highlights the importance of Aβ oligomers and emphasizes the validity of the model to study AD-like early processes, with potentially predictive value.

Keywords: Alzheimer disease; Camk2b; Grin2b; amyloid beta-precursor protein; cognitive dysfunction; long-term memory; neuronal plasticity; social behavior alterations.

Apelin is the endogenous ligand for APJ, a G-protein-coupled receptor. Apelin gene and protein are widely distributed in the central nervous system and peripheral tissues. The role of apelin in chronic inflammatory pain is still unclear. In the present study, a mouse model of complete Freund's adjuvant (CFA)-induced inflammatory pain was utilized, and the paw withdrawal latency/threshold in response to thermal stimulation and Von Frey filament stimulation were recorded after intrathecal (i.t.) injection of apelin-13 (0.1, 1, and 10 nmol/mouse). The mRNA and protein expression, concentration of glutamic acid (Glu), and number of c-Fos immunol staining in lumbar spinal cord (L4/5) were determined. The results demonstrated that Apln gene expression in the lumbar spinal cord was down-regulated in the CFA pain model. Apelin-13 (10 nmol/mouse, i.t.) alleviated CFA-induced inflammatory pain, and it exhibited a more potent antinociceptive effect than apelin-36 and (pyr)apelin-13. The antinociception of apelin-13 could be blocked by APJ antagonist apelin-13(F13A). I.T. apelin-13 attenuated the increased levels of Aplnr, Grin2b, Camk2d, and c-Fos genes expression, Glu concentration, and NMDA receptor 2B (GluN2B) protein expression caused by CFA. Apelin-13 significantly reduced the number of Fos-positive cells in laminae III and IV/V of the dorsal horn. This study indicated that i.t. apelin-13 exerted an analgesic effect against inflammatory pain, which was mediated by activation of APJ, and inhibition of Glu/GluN2B function and neural activity of the spinal dorsal horn.

Keywords: Fos; NMDA receptor; apelin; inflammatory pain; spinal cord.

Objective: The aim of this study was to comprehensively explore the relationship between genetic variations within GRIN2A, GRIN2B, GRIK1, GRIK4, GRID2, and ADHD. Method: Genotyping was performed with the Sequenom MassARRAY system in a two-stage case-control study. ADHD symptoms were assessed using the Swanson, Nolan, and Pelham version IV scale and the Integrated Visual and Auditory Continuous Performance Test. In silico analysis was performed with website resources. Results: GRID2 rs1385405 showed a significant association with ADHD risk in the codominant model (OR = 2.208, 95% CI = [1.387, 3.515]) in the first stage and in the codominant model (OR = 1.874, 95% CI = [1.225, 2.869]) and recessive model (OR = 1.906, 95% CI = [1.265, 2.873]) in the second stage and related to inattention and hyperactivity symptom. In addition, rs1385405 disturbed the activity of exonic splicing enhancer and mediated GRID2 gene expression in the frontal cortex. Conclusion: our data provided evidence for the participation of GRID2 variants in conferring the risk of ADHD.

Although substantial heritability has been reported and candidate genes have been identified, we are far from understanding the etiopathogenetic pathways underlying developmental dyslexia (DD). Reading-related endophenotypes (EPs) have been established. Until now it was unknown whether they mediated the pathway from gene to reading (dis)ability. Thus, in a sample of 223 siblings from nuclear families with DD and 79 unrelated typical readers, we tested four EPs (i.e., rapid auditory processing, rapid automatized naming, multisensory nonspatial attention and visual motion processing) and 20 markers spanning five DD-candidate genes (i.e., DYX1C1, DCDC2, KIAA0319, ROBO1 and GRIN2B) using a multiple-predictor/multiple-mediator framework. Our results show that rapid auditory and visual motion processing are mediators in the pathway from ROBO1-rs9853895 to reading. Specifically, the T/T genotype group predicts impairments in rapid auditory and visual motion processing which, in turn, predict poorer reading skills. Our results suggest that ROBO1 is related to reading via multisensory temporal processing. These findings support the use of EPs as an effective approach to disentangling the complex pathways between candidate genes and behavior.

Keywords: candidate genes; developmental dyslexia; endophenotypes; mediation; multisensory temporal processing.

Dopamine (DA) is an important neuromodulator of motor control across species. In zebra finches, DA levels vary in song nucleus Area X depending upon social context. DA levels are high and song output is less variable when a male finch sings to a female (female directed, FD) compared to when he is singing by himself (undirected, UD). DA modulates glutamatergic input onto cortico-striatal synapses in Area X via N-methyl-d-aspartate (NMDA) and DA receptor mechanisms, but the relationship to UD vs. FD song output is unclear. Here, we investigate the expression of molecular markers of dopaminergic and glutamatergic synaptic transmission (tyrosine hydroxylase - TH, alpha-synuclein - α-syn) and plasticity (NMDA 2B receptor - GRIN2B) following singing (UD vs. FD) and non-singing states to understand the molecular mechanisms driving differences in song output. We identified relationships between protein levels for these biomarkers in Area X based on singing state and the amount of song, measured as the number of motifs and time spent singing. UD song amount drove increases in TH, α-syn, and NMDA 2B receptor protein levels. By contrast, the amount of FD song did not alter TH and NMDA 2B receptor expression. Levels of α-syn showed differential expression patterns based on UD vs. FD song, consistent with its role in modulating synaptic transmission. We propose a molecular pathway model to explain how social context and amount of song are important drivers of molecular changes required for synaptic transmission and plasticity.

Background: Type 1 diabetes (T1D) is a serious threat to childhood life and has fairly complicated pathogenesis. Profound attempts have been made to enlighten the pathogenesis, but the molecular mechanisms of T1D are still not well known.

Methods: To identify the candidate genes in the progression of T1D, expression profiling by high throughput sequencing dataset GSE123658 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and gene ontology (GO) and pathway enrichment analyses were performed. The protein-protein interaction network (PPI), modules, target gene - miRNA regulatory network and target gene - TF regulatory network analysis were constructed and analyzed using HIPPIE, miRNet, NetworkAnalyst and Cytoscape. Finally, validation of hub genes was conducted by using ROC (Receiver operating characteristic) curve and RT-PCR analysis. A molecular docking study was performed.

Results: A total of 284 DEGs were identified, consisting of 142 up regulated genes and 142 down regulated genes. The gene ontology (GO) and pathways of the DEGs include cell-cell signaling, vesicle fusion, plasma membrane, signaling receptor activity, lipid binding, signaling by GPCR and innate immune system. Four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell-cell signaling, cytokine signaling in immune system, signaling by GPCR and innate immune system. ROC curve and RT-PCR analysis showed that EGFR, GRIN2B, GJA1, CAP2, MIF, POLR2A, PRKACA, GABARAP, TLN1 and PXN might be involved in the advancement of T1D. Molecular docking studies showed high docking score.

Conclusions: DEGs and hub genes identified in the present investigation help us understand the molecular mechanisms underlying the advancement of T1D, and provide candidate targets for diagnosis and treatment of T1D.

Keywords: bioinformatics; differentially expressed genes; enrichment analysis; pathways; type 1 diabetes.

Background: Zinc is an essential trace element and a number of studies have identified the importance of zinc in neurodevelopment in children. However, epidemiologic data on the associations of zinc and genetic susceptibility with the risk of dyslexia are limited. We aimed to investigate whether genetic polymorphisms in GRIN2B genes modify the association between zinc levels and dyslexia risk.

Methods: A case-control study of 240 dyslexic children and 230 healthy controls was conducted in Wuhan, Hangzhou and Jining city in China from April 2017 to April 2018. Zinc concentrations in urine samples were measured with inductively coupled plasma-mass spectrometry (ICPMS). Multiple imputation was used to impute missing values of covariates. We applied multivariable logistic regression models to evaluate the effect in the study.

Results: After adjustment for potential confounders, we observed the associations of urinary zinc with dyslexia risk were modified by rs1805502 (P_interaction = 0.048) in gene GRIN2B. About 2-fold increase in creatinine-corrected zinc levels was significantly related to a reduced risk of dyslexia [odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.29, 0.95 in rs1805502 mutation carriers].

Conclusions: The associations between zinc levels and dyslexia risk were modified by polymorphism of rs1805502 in gene GRIN2B.

Keywords: Dyslexia; Gene-environment interaction; Zinc.

Exercise is believed to be beneficial for skeletal muscle functions across all ages. Regimented exercise is often prescribed as an effective treatment/prophylaxis for age-related loss of muscle mass and functions known as sarcopenia, and plays an important role in the maintenance of mobility and functional independence in the elderly. However, response to exercise changes with aging, with a shift from a predominantly anabolic response resulting in limited gain of muscle strength and endurance. These changes likely reflect age-dependent alterations in transcriptional response underlying the muscular adaptation to exercise. The exact changes in gene expression accompanying exercise, however, are largely unknown, and elucidating them is of a great clinical interest for understanding and optimizing the exercise-based therapies for sarcopenia. In order to characterize the exercise-induced transcriptomic changes in aged muscle, a paired-end RNA sequencing was performed on the rRNA-depleted total RNA extracted from the gastrocnemius muscles of 24 months-old mice after 8 weeks of regimented exercise (exercise group) or no formal exercise program (sedentary group). Differential gene expression analysis of aged skeletal muscle revealed upregulations in the group of genes involved in neurotransmission and neuroexcitation, as well as equally notable absence of anabolic gene upregulations in the exercised group. In particular, genes encoding the transporters and receptor components of glutaminergic transmission were significantly upregulated in exercised muscles, as exemplified by Gria 1, Gria 2 and Grin2c encoding glutamate receptor 1, 2 and 2C respectively, Grin1 and Grin2b encoding N-methyl-d-aspartate receptors (NMDARs), Nptx1 responsible for glutaminergic receptor clustering, and Slc1a2 and Slc17a7 regulating synaptic uptake of glutamate. These changes were accompanied by an increase in the post-synaptic density of NMDARs and acetylcholine receptors (AChRs), as well as their innervation at neuromuscular junctions (NMJs). These results suggest that neural responses predominate the adaptive response of aged skeletal muscle to exercise, and indicate a possibility that glutaminergic transmission at NMJs may be present and responsible for synaptic protection and neural remodeling accompanying the exercise-induced functional enhancement in aged skeletal muscle. In addition, the absence of upregulations in the anabolic pathways highlights them as the area of potential pharmacological targeting for optimizing exercise-led sarcopenia therapy.

Keywords: Aging; Differentially expressed genes; Exercise; Sarcopenia; Skeletal muscle.

Aim: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only.

Method: We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male).

Results: We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) (p<1.86×10^-10 , odds ratio 37.22, 95% confidence interval 8.60-337.0).

Interpretation: We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A, can be implicated in intellectual disability without epilepsy; in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause.

The Chinese Qingyu pig is a typical domestic fatty pig breed and an invaluable indigenous genetic resource in China. Compared with Landrace pig, Qingyu pig has unique meat characteristics, including muscle development, intramuscular fat, and other meat quality traits. At present, few studies have explored the epigenetic difference due to DNA methylation between Qingyu pig and Landrace pig. In this study, 30 Qingyu pigs and 31 Landrace pig were subjected to reduced representation bisulfite sequencing (RRBS). A genome wide differential DNA methylation analysis was conducted. Six genomic regions, including regions on sus scrofa chromosome (SSC) 1: 266.09-274.23Mb, SSC5:0.88-10.68Mb, SSC8:41.23-48.51Mb, SSC12:45.43-54.38Mb, SSC13:202.15-207.95Mb, and SSC14:126.43-139.85Mb, were regarded as key regions that may be associated with phenotypic differences between Qingyu pig and Landrace pig. Furthermore, according to the further analysis, 5 differential methylated genes (ADCY1, FUBP3, GRIN2B, KIT, and PIK3R6) were deemed as key candidate genes that might be associated with meat characteristics. Our findings provide new insights into the difference of DNA methylation between Qingyu pig and Landrace pig. The results enrich the epigenetic research of Chinese Qingyu pigs.

Background: Pediatric dental caries is common among Arab children, however we are still searching for possible genes and molecular mechanisms that influence caries development.

Aim: To identity genetic predispositions of dental caries among Saudi children with high DMFT (Decayed, Missing, and Filled Teeth).

Design: This case-control study analysed putative functional exonic-variants (n = 243,345) to study the molecular genetics of pediatric caries with high dmft index, 8.75 ± 4.16 on Arab-ancestry subjects with primary dentition (n = 111; 76 cases, dmft>5 and 35 controls, dmft = 0).

Results: Pediatric caries is significantly associated with single nucleotide polymorphisms (SNP) in the GRIN2B-rs4764039C (p-value = 2.03 × 10^-08) and CFH-rs1065489G (p-value = 8.26 × 10^-08) genes, even after Bonferroni correction. Irregular tooth brushing habits (p = 0.0404) and irregular dental visits (p = 0.0050) are significantly associated with caries. Functional enrichment analysis of significant genes is associated with calcium-activated chloride channel, Staphylococcus aureus infection, and N-linked glycosylation.

Conclusion: Genetic predispositions are found to be significantly associated with the high prevalence of pediatric caries, which is a disorder of multigene-environment interaction. The significant functional exonic variants identified can be biomarkers for the early diagnosis of pediatric dental caries in Arabs.

Keywords: Biomarker; Dental caries; Genotype; Haplotype; Multigene-environment interaction; SNPs; Tooth brushing habits.

OBJECTIVE

Clinical trials with healthy volunteers are a useful model for evaluating safety and tolerability, without the interference of concomitant diseases and drugs. The present study aims to improve our understanding of antipsychotic-related adverse reactions (ARs) and their possible association with common genetic variants of pharmacodynamic proteins such as neurotransmitter receptors/transporters.

METHODS

A total of eight polymorphisms located in seven pharmacodynamic-related genes (SCL6A4, MDR1, 5HT2A, DRD2, DRD3, COMT and GRIN2B) were genotyped in a cohort of 211 healthy volunteers who received a single dose of risperidone (1 mg), olanzapine (5 mg) or quetiapine (25 mg).

RESULTS

Interestingly, a significant association was found between the incidence of neurological ARs and specific polymorphisms in key genes (DRD2 and SCL6A4).

CONCLUSIONS

Genetic variants in pharmacodynamic genes could represent valuable markers of AR risk and antipsychotic safety. Original submitted 7 February 2013; Revision submitted 3 June 2013.