Glutamate receptor gene GRIN2A, coffee, and Parkinson disease.
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ABSTRACT:
SUBMITTER: Hamza TH
PROVIDER: S-EPMC4238944 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
Publications
Glutamate receptor gene GRIN2A, coffee, and Parkinson disease.
Hamza Taye H TH Hill-Burns Erin M EM Scott William K WK Vance Jeffrey M JM Factor Stewart A SA Zabetian Cyrus P CP Payami Haydeh H
PLoS genetics 20141120 11
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Project description:Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df)?=?10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR?=?0.43; P?=?6×10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: OR(Replication)?=?0.59, P(Replication)?=?10(-3); OR(Pooled)?=?0.51, P(Pooled)?=?7×10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P?=?3×10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P?=?6×10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5×10(-8) in GWAIS, and OR?=?0.41, P?=?3×10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.
| S-EPMC3158052 | biostudies-literature
Project description: Not available
| S-EPMC4238979 | biostudies-literature
Project description:A complex interplay between genetic and environmental factors is thought to be involved in the etiology of Parkinson's disease (PD). A recent genome-wide association and interaction study (GWAIS) identified GRIN2A, which encodes an NMDA-glutamate-receptor subunit involved in brain's excitatory neurotransmission, as a PD genetic modifier in inverse association with caffeine intake. Here in, we attempted to replicate the reported association of a single nucleotide polymorphism, GRIN2A_rs4998386, and its interaction with caffeine intake with PD in patient-control study in an ethnically homogenous population in southeastern Sweden, as consistent and independent genetic association studies are the gold standard for the validation of genome-wide association studies. All the subjects (193 sporadic PD patients and 377 controls) were genotyped, and the caffeine intake data was obtained by questionnaire. We observed an association between rs4998386 and PD with odds ratio (OR) of 0.61, 95% confidence intervals (CI) of 0.39-0.96, p = 0.03, under a model excluding rare TT allele. There was also a strong significance in joint effects of gene and caffeine on PD risk (TC heavy caffeine vs. CC light caffeine: OR = 0.38, 95%CI = [0.20-0.70], p = 0.002) and gene-caffeine interaction (OR = 0.998, 95%CI = [0.991-0.999], p<0.001). Overall, our results are in support of the findings of the GWAIS and provided additional evidence indicating PD protective effects of coffee drinking/caffeine intake as well as the interaction with glutamate receptor genotypes.
| S-EPMC4051678 | biostudies-literature
Project description:ObjectiveDopaminergic neuronal degeneration seen in Parkinson's disease (PD) might result from a single nucleotide polymorphism (SNP) in the glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) gene. We thus performed a meta-analysis exploring the relationship between the rs4998386 SNP of the GRIN2A gene and PD susceptibility.MethodsWe searched PubMed, EMBASE, Web of Science, Google Scholar, and China National Knowledge Infrastructure for studies published between January 2005 and January 2019. The association between the rs4998386 polymorphism and PD susceptibility was evaluated by calculating the pooled odds ratios (ORs) and 95% confidence intervals (CIs).ResultsMeta-analysis results did not show a significant association between the rs4998386 polymorphism of the GRIN2A gene and PD susceptibility when assuming an allelic model (OR, 0.90; 95% CI, 0.76-1.07; P = .22; I 2 = 53%), a dominant model (OR, 0.96; 95% CI, 0.82-1.12; P = .62; I 2 = 64%), or a recessive model (OR, 1.14; 95% CI, 0.93-1.38; P = .22; I 2 = 0%).ConclusionOur meta-analysis found that the rs4998386 polymorphism of the GRIN2A gene is not associated with risk of PD in either Europeans or white Americans. However, large sample studies with different ethnicities should be conducted to establish the role of the rs4998386 polymorphism in PD pathophysiology.
| S-EPMC6880709 | biostudies-literature
Project description:Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegeneration disorders including multiple sclerosis (MS), Alzheimer disease (AD), and recently Parkinson disease (PD). Given the sparse data on PD, we conducted a two-stage study to evaluate the genetic effects of VDR in PD. In the discovery stage, 30 tagSNPs in VDR were tested for association with risk as a discrete trait and age-at-onset (AAO) as a quantitative trait in 770 Caucasian PD families. In the validation stage, 18 VDR SNPs were tested in an independent Caucasian cohort (267 cases and 267 controls) constructed from a genome-wide association study (GWAS). In the discovery dataset, SNPs in the 5' end of VDR were associated with both risk and AAO with more significant evidence of association with AAO (P= 0.0008-0.02). These 5' SNPs were also associated with AD in another study. In the validation dataset, SNPs in the 3' end of VDR were associated with AAO (P= 0.003) but not risk. The 3' end SNP has been associated with both MS and AD in previous studies. Our findings suggest VDR as a potential susceptibility gene and support an essential role of vitamin D in PD.
| S-EPMC3077063 | biostudies-literature
Project description:BACKGROUND:Caffeine intake has been inversely associated with Parkinson's disease (PD) risk. This relationship may be modified by polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2), but the results of previous studies have been inconsistent. METHOD:We examined the interaction of caffeine intake with GRIN2A-rs4998386 and CYP1A2-rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. Matching factors included cohort, birth year, source of DNA, date of DNA collection, and race. Relative risks and 95% confidence intervals were estimated using conditional logistic models. Interactions were tested both on the multiplicative scale and on the additive scale. RESULTS:Overall, caffeine intake was associated with a lower PD risk (adjusted relative risk for highest versus lowest tertile = 0.70; 95% confidence interval, 0.57-0.86; p < .001). In analyses stratified by the GRIN2A-rs4998386 genotype, the multivariable-adjusted relative risk of PD comparing the highest to the lowest tertile of caffeine was 0.69 (95% confidence interval, 0.55-0.88; p < .01) among individuals homozygous for the C allele, and 0.85 (95% confidence interval, 0.55-1.32; p = .47; pRERI = .43) among carriers for the T allele. Interactions between caffeine and GRIN2A were not significant in either the multiplicative or additive scales. We also did not observe significant interactions for CYP1A2-rs762551 and incident PD risk. CONCLUSION:Our findings do not support the hypothesis of an interaction between the GRIN2A-rs4998386 or CYP1A2-rs762551 polymorphism and caffeine intake in determining PD risk. © 2018 International Parkinson and Movement Disorder Society.
| S-EPMC5839986 | biostudies-literature
Project description:The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA) receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs) with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT)26 repeats (rs3219790) in the heroin addiction group was significantly higher than that in the control group (?(2) = 5.360, P = 0.021). The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3) were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction). Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487) had nominally significant P values for association (P<0.05), but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6) and T-T (block 10) haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003). These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.
| S-EPMC3733659 | biostudies-literature
Project description:BackgroundIgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.MethodsNMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.ResultsThe frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.ConclusionIt is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
| S-EPMC6446289 | biostudies-literature
Project description:Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.
| S-EPMC5386398 | biostudies-literature
Project description:ObjectiveTo delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A.MethodsWe analyzed the speech phenotype associated with GRIN2A mutations in 11 individuals, aged 16 to 64 years, from 3 families. Standardized clinical speech assessments and perceptual analyses of conversational samples were conducted.ResultsIndividuals showed a characteristic phenotype of dysarthria and dyspraxia with lifelong impact on speech intelligibility in some. Speech was typified by imprecise articulation (11/11, 100%), impaired pitch (monopitch 10/11, 91%) and prosody (stress errors 7/11, 64%), and hypernasality (7/11, 64%). Oral motor impairments and poor performance on maximum vowel duration (8/11, 73%) and repetition of monosyllables (10/11, 91%) and trisyllables (7/11, 64%) supported conversational speech findings. The speech phenotype was present in one individual who did not have seizures.ConclusionsDistinctive features of dysarthria and dyspraxia are found in individuals with GRIN2A mutations, often in the setting of epilepsy-aphasia syndromes; dysarthria has not been previously recognized in these disorders. Of note, the speech phenotype may occur in the absence of a seizure disorder, reinforcing an important role for GRIN2A in motor speech function. Our findings highlight the need for precise clinical speech assessment and intervention in this group. By understanding the mechanisms involved in GRIN2A disorders, targeted therapy may be designed to improve chronic lifelong deficits in intelligibility.
| S-EPMC4335991 | biostudies-literature