Association of μ-opioid receptor subunit gene and idiopathic generalized epilepsy

Wilkie, Hazel; Osei-Lah, Abena; Chioza, Barry A.; Nashef, Lina; McCormick, David; Asherson, Philip; Makoff, Andrew

doi:10.1212/wnl.59.5.724

Cited by 18 publications

(8 citation statements)

References 17 publications

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“…SNPs in the OPRM1 gene have been investigated for their involvement in various other disorders (Supplementary table 3) [33, [153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170]. The A118G SNP is the only variation that has been associated with susceptibility to disorders and related traits in numerous studies.…”

Section: Association Of Snps In the Oprm1 Gene With Other Disordersmentioning

confidence: 99%

Pharmacogenomics of the Human µ-Opioid Receptor

Kasai

Ikeda

2011

Pharmacogenomics

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The µ-opioid receptor is a primary target for clinically important opioid analgesics, including morphine, fentanyl and methadone. Many genetic variations have been identified in the human µ-opioid receptor MOP gene (OPRM1), and their implications have been reported in the effects of opioid drugs and susceptibility to drug dependence. Interestingly, agonistic and antagonistic opioid effects are inversely associated with the A118G polymorphism genotype. The A118G polymorphism may also be associated with substance dependence and susceptibility to other disorders, including epilepsy and schizophrenia. The IVS1+A21573G, IVS1-T17286C, and TAA+A5359G polymorphisms in the OPRM1 gene may be associated with alcohol, opioid and tobacco dependence, respectively. However, some studies have failed to confirm the correlations between the polymorphisms and opioid effects and substance dependence. Further studies are needed to elucidate the molecular mechanisms underlying the effects of OPRM1 polymorphisms.

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Section: Association Of Snps In the Oprm1 Gene With Other Disordersmentioning

confidence: 99%

Pharmacogenomics of the Human µ-Opioid Receptor

Kasai

Ikeda

2011

Pharmacogenomics

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“…The majority of the studies have been negative, and thus no further replication attempts have been made on these. No clear susceptibility gene for IGE has yet been identified, save possibly the opioid receptor μ‐subunit gene (50,51).…”

Section: Association Studies In Idiopathic Generalized Epilepsiesmentioning

confidence: 99%

Genetic Association Studies in Epilepsy: “The Truth Is Out There”

2004

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Summary: Success has been achieved in identifying many mutations in rare monogenic epilepsy syndromes by using linkage analysis, but dissecting the genetic basis of common epilepsy syndromes has proven more difficult. Common epilepsies are genetically complex disorders believed to be influenced by variation in several susceptibility genes. Association studies can theoretically identify these genes, but despite more than 50 association studies in epilepsy, no consistent or convincing susceptibility genes have emerged, leading to scepticism about the association-study approach. We review the results of existing association studies in focal epilepsies, generalized epilepsies, febrile seizures, and epilepsy pharmacogenetics. By using an illustrative example, we discuss how methodologic issues of sample size, selection of appropriate controls, population stratification, and significance thresholds can lead to bias and falsepositive associations; the importance of biologic plausibility also is emphasized. Newer methodologic refinements for association studies, such as use of two control groups, genomic control, haplotyping, and use of two independent datasets, are discussed. A summary of existing guidelines and a checklist for planning and appraising such association studies in epilepsy is presented. We remain cautiously optimistic that with methodologic refinements and multicenter collaborations with large sample sizes, association studies will ultimately be useful in dissecting the genetic basis of common epilepsy syndromes.

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“…We have observed significant allele frequency differences between the two centres for other SNPs. 35 While it remains possible that the findings reported here result from mere chance alone, this is highly unlikely given the lack of LD between one of the SNPs associated with IGE and the other four.…”

Section: Discussionmentioning

confidence: 84%

Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy

Chioza¹,

Osei-Lah

Nashef

et al. 2002

Eur J Hum Genet

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Idiopathic generalised epilepsy (IGE) is a common form of epilepsy, including several defined and overlapping syndromes, and likely to be due to the combined actions of mutations in several genes. In a recent study we investigated the calcium channel gene CACNA1A for involvement in IGE, unselected for syndrome, by means of association studies using several polymorphisms within the gene. We reported a highly significant case/control association with a silent single nucleotide polymorphism (SNP) in exon 8 that we confirmed by within-family analyses. In this present study we screened the gene for novel SNPs within 25 kb of exon 8, which have enabled us to define the critical region of CACNA1A in predisposing to IGE. Several intronic SNPs were identified and three, within 1.5 kb of exon 8 and in strong linkage disequilibrium with each other and with the original SNP, were significantly associated with IGE (P=0.00029, P=0.0015 and P=0.010). The associations were not limited to an IGE syndrome or other subgroup. Another SNP, 25 kb away, in intron 6 was also significantly associated with IGE (P=0.0057) but is not in linkage disequilibrium with the SNPs around exon 8. Haplotype predictions revealed even more significant associations (3-marker haplotype: P510 76 ). Logistic regression showed that all the data can be explained by two of the SNPs, which is consistent with two functionally significant variants being responsible for all five associations, although a single variant cannot be excluded. The functionally significant variant(s) are unlikely to be exonic and suggests an effect on expression or alternative splicing.

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Association of μ-opioid receptor subunit gene and idiopathic generalized epilepsy

Cited by 18 publications

References 17 publications

Pharmacogenomics of the Human µ-Opioid Receptor

Pharmacogenomics of the Human µ-Opioid Receptor

Genetic Association Studies in Epilepsy: “The Truth Is Out There”

Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy

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