Skip to main content

Advertisement

SpringerLink
Log in

Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Gamma-aminobutyric acid receptor (GABA-A) is the most common receptor of fast synaptic inhibition in the human brain. Gamma protein encoded by the GABRG2 gene is one of the subunits of the GABA-A receptor, which plays an essential role in the function of this receptor. Several studies have identified various febrile seizure (FS) and epilepsy risk variants of GABRG2 gene in different populations, but some others did not support these results. The aim of this case–control study is to investigate whether GABRG2 polymorphisms contribute to susceptibility for FS and epilepsy in pooled data of three cohorts, from Malaysia (composed of Malay, Chinese, and Indian), Hong Kong, and Korea. Furthermore, the pooled dataset of these cohorts with previous reports were meta-analyzed for determining the risk effect size of the rs211037 polymorphism on FS and symptomatic epilepsy (SE). The rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750 polymorphisms were genotyped in the 6442 subjects (1729 epilepsy and 4713 controls). Results of the case–control study showed associations between rs211037 and the risk of SE in the pooled data from all cohorts (T vs. C, p = 3 × 10−5, and TT vs. CC, p = 2 × 10−5) and the risk of partial seizure in the combined data of Malaysia and Hong Kong (both T vs. C and TT vs. CC, p = 2 × 10−6). The rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes were also associated with susceptibility to SE in Chinese. Meta-analysis of all Asians identified association between rs211037 and FS and SE (T vs. C, p = 4 × 10−4, and p = 4 × 10−3, respectively). In conclusion, rs211037 alone may be a risk factor for FS, partial seizure, and SE, and in linkage disequilibrium with rs210987 can contribute to FS and SE in Asians, particularly in Chinese.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Banerjee PN, Filippi D, Allen HW (2009) The descriptive epidemiology of epilepsy—a review. Epilepsy Res 85(1):31–45

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hauser WA, Mohr JP (2011) Seizures, epilepsy, and vascular malformations. Neurology 76(18):1540–1541

    Article  PubMed  Google Scholar 

  3. Badawy RA, Harvey AS, Macdonell RA (2009) Cortical hyperexcitability and epileptogenesis: understanding the mechanisms of epilepsy—part 2. J Clin Neurosci 16(4):485–500

    Article  PubMed  Google Scholar 

  4. Guan Z, Saraswati S, Adolfsen B et al (2005) Genome-wide transcriptional changes associated with enhanced activity in the Drosophila nervous system. Neuron 48(1):91–107

    Article  CAS  PubMed  Google Scholar 

  5. Mizielinska S, Greenwood S, Connolly CN (2006) The role of GABAA receptor biogenesis, structure and function in epilepsy. Biochem Soc Trans 34(Pt 5):863–867

    Article  CAS  PubMed  Google Scholar 

  6. Benarroch EE (2007) GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology 68(8):612–4

    Article  CAS  PubMed  Google Scholar 

  7. Wilcox AS, Warrington JA, Gardiner K et al (1992) Human chromosomal localization of genes encoding the gamma 2 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proc Natl Acad Sci U S A 89(13):5857–5861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baulac S, Huberfeld G, Gourfinkel-An I et al (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 28(1):46–8

    CAS  PubMed  Google Scholar 

  9. Hirose S (2014) Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res 213:55–85

    Article  PubMed  Google Scholar 

  10. Kang JQ, Macdonald RL (2009) Making sense of nonsense GABA(A) receptor mutations associated with genetic epilepsies. Trends Mol Med 15(9):430–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wallace RH, Marini C, Petrou S et al (2001) Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 28(1):49–52

    CAS  PubMed  Google Scholar 

  12. Tian M, Macdonald RL (2012) The intronic GABRG2 mutation, IVS6+2T->G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated γ2 subunit. J Neurosci 32(17):5937–5952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mulligan MK, Wang X, Adler AL et al (2012) Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation. PLoS One 7(4):e34586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chou IC, Peng CT, Huang CC et al (2003) Association analysis of gamma 2 subunit of gamma- aminobutyric acid type A receptor polymorphisms with febrile seizures. Pediatr Res 54:26–29

    Article  CAS  PubMed  Google Scholar 

  15. Madia F, Gennaro E, Cecconi M et al (2003) No evidence of GABRG2 mutations in severe myoclonic epilepsy of infancy. Epilepsy Res 53:196–200

    Article  CAS  PubMed  Google Scholar 

  16. Nakayama J, Hamano K, Noguchi E et al (2003) Failure to find causal mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients. Neurosci Lett 343:117–120

    Article  CAS  PubMed  Google Scholar 

  17. Kinirons P, Cavalleri GL, Shahwan A et al (2006) Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs. Epilepsy Res 70:229–238

    Article  CAS  PubMed  Google Scholar 

  18. Ma S, Abou-Khalil B, Blair MA et al (2006) Mutations in GABRA1, GABRA5, GABRG2 and GABRD receptor genes are not a major factor in the pathogenesis of familial focal epilepsy preceded by febrile seizures. Neurosci Lett 394:74–78

    Article  CAS  PubMed  Google Scholar 

  19. Chou IC, Lee CC, Tsai CH et al (2007) Association of GABRG2 polymorphisms with idiopathic generalized epilepsy. Pediatr Neurol 36:40–44

    Article  PubMed  Google Scholar 

  20. Salam SM, Rahman HM, Karam RA (2012) GABRG2 gene polymorphisms in Egyptian children with simple febrile seizures. Indian J Pediatr 79:1514–1516

    Article  PubMed  Google Scholar 

  21. Balan S, Sathyan S, Radha SK et al (2013) GABRG2 rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenet Genomics 23(11):605–610

    Article  CAS  PubMed  Google Scholar 

  22. Gitaí LL, de Almeida DH, Born JP et al (2012) Lack of association between rs211037 of the GABRG2 gene and juvenile myoclonic epilepsy in Brazilian population. Neurol India 60(6):585–588

    Article  PubMed  Google Scholar 

  23. Haerian BS, Baum L (2013) GABRG2 rs211037 polymorphism and epilepsy: a systematic review and meta-analysis. Seizure 22(1):53–58

    Article  PubMed  Google Scholar 

  24. Wang X, Xu M, Lizhong D (2007) Association analysis of gamma2 subunit of gamma-aminobutyric acid (GABA) type A receptor and voltage-gated sodium channel type II alpha-polypeptide gene mutation in southern Chinese children with febrile seizures. J Child Neurol 22(6):714–719

    Article  Google Scholar 

  25. Fendri-Kriaa N, Kammoun F, Rebai A et al (2009) Genetic screening of two Tunisian families with generalized epilepsy with febrile seizures plus. Eur J Neurol 16(6):697–704

    Article  CAS  PubMed  Google Scholar 

  26. Panayiotopoulos CP (2012) The new ILAE report on terminology and concepts for the organization of epilepsies: critical review and contribution. Epilepsia 53(3):399–404

    Article  PubMed  Google Scholar 

  27. Guo Y, Baum LW, Sham PC et al (2012) Two-stage genome-wide association study identifies variants in CAMSAP1L1 as susceptibility loci for epilepsy in Chinese. Hum Mol Genet 21:1184–1189

    Article  CAS  PubMed  Google Scholar 

  28. Halász P, Rásonyi G (2004) Neuroprotection and epilepsy. Adv Exp Med Biol 541:91–109

    Article  PubMed  Google Scholar 

  29. Patterson JL, Carapetian SA, Hageman JR et al (2013) Febrile seizures. Pediatr Ann 42(12):249–54

    Article  PubMed  Google Scholar 

  30. Laurie DJ, Wisden W, Seeburg PH (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci 12(11):4151–4172

    CAS  PubMed  Google Scholar 

  31. Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 25(23):5511–5520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Macdonald RL, Kang JQ, Gallagher MJ (2010) Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol 588(Pt 11):1861–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kilic U, Gok O, Bacaksiz A et al (2014) SIRT1 gene polymorphisms affect the protein expression in cardiovascular diseases. PLoS One 9(2):e90428

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yang SY, He XY, Miller D (2007) HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids. Mol Genet Metab 92(1-2):36–42

    Article  CAS  PubMed  Google Scholar 

  35. Göthert M, Propping P, Bönisch H et al (1998) Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role. Ann N Y Acad Sci 861:26–30

    Article  PubMed  Google Scholar 

  36. Wang DD, Kriegstein AR (2009) Defining the role of GABA in cortical development. J Physiol 587(Pt 9):1873–1879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Naylor DE, Liu H, Wasterlain CG (2005) Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 25(34):7724–7733

    Article  CAS  PubMed  Google Scholar 

  38. Sauna ZE, Kimchi-Sarfaty C (2011) Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet 12(10):683–691

    Article  CAS  PubMed  Google Scholar 

  39. Coop G, Wen X, Ober C et al (2008) High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319:1395–1398

    Article  CAS  PubMed  Google Scholar 

  40. Spencer CC, Deloukas P, Hunt S et al (2006) The influence of recombination on human genetic diversity. PLoS Genet 2:e148

    Article  PubMed  PubMed Central  Google Scholar 

  41. Keinan A, Reich D (2010) Human population differentiation is strongly correlated with local recombination rate. PLoS Genet 6(3):e1000886

    Article  PubMed  PubMed Central  Google Scholar 

  42. Choudhury A, Hazelhurst S, Meintjes A et al (2014) Population-specific common SNPs reflect demographic histories and highlight regions of genomic plasticity with functional relevance. BMC Genomics 15:437

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the subjects from Malaysia, Hong Kong, and Korea for their participation in this study, as well as the staff of the hospitals for their assistance in recruiting patients.

Author information

Authors and Affiliations

  1. Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Lembah Pantai, 59100, Kuala Lumpur, Malaysia

    Batoul Sadat Haerian & Zahurin Mohamed

  2. School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Larry Baum

  3. Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Patrick Kwan

  4. Department of Psychiatry and The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China

    Stacey S. Cherny

  5. Department of Pharmacology and Pharmacogenomics Research Center, College of Medicine, Inje University, Busan, South Korea

    Jae-Gook Shin

  6. Department of Neurology, Haeundae Paik Hospital, Inje University, Busan, South Korea

    Sung Eun Kim

  7. Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, South Korea

    Bok-Ghee Han

  8. Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

    Hui Jan Tan & Azman Ali Raymond

  9. Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Chong Tin Tan

Authors
  1. Batoul Sadat Haerian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Larry Baum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Kwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stacey S. Cherny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jae-Gook Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sung Eun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bok-Ghee Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui Jan Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Azman Ali Raymond
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chong Tin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zahurin Mohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Batoul Sadat Haerian or Larry Baum.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Funding

This study was supported by Malaysian Grants HIR MOHE E000025-20001 and RG 520/13HTM and the Research Grants Council of the Hong Kong Special Administrative Region, China grants HKU7623/08M, HKU7747/07M, and CUHK4466/06M. Korean data was supported in part from the Korea Biobank Project (4851-307) and the Korean Genome and Epidemiology Study (4801-302).

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

Genotype, allele, and halotype of all types of epilepsy and FS and summary of the previous published studies (XLS 208 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haerian, B.S., Baum, L., Kwan, P. et al. Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis. Mol Neurobiol 53, 5457–5467 (2016). https://doi.org/10.1007/s12035-015-9457-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9457-y

Keywords

Search

Navigation