Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy

Larry Baum, Batoul Sadat Haerian, Ho Keung Ng, Virginia C N Wong, Ping Wing Ng, Colin H T Lui, Ngai Chuen Sin, Chunbo Zhang, Brian Tomlinson, Gary Wing Kin Wong, Hui Jan Tan, Raymond Azman Ali, Zahurin Mohamed, Patrick Kwan

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Abstract

High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r 2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.

Original languageEnglish
Pages (from-to)651-659
Number of pages9
JournalHuman Genetics
Volume133
Issue number5
DOIs
Publication statusPublished - 2014

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Voltage-Gated Sodium Channels
Case-Control Studies
Epilepsy
Odds Ratio
Genes
Alleles
Malaysia
Hong Kong
Genotype
Febrile Seizures
Sodium Channels
Linkage Disequilibrium
Brain
Action Potentials
Meta-Analysis
Neurons

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. / Baum, Larry; Haerian, Batoul Sadat; Ng, Ho Keung; Wong, Virginia C N; Ng, Ping Wing; Lui, Colin H T; Sin, Ngai Chuen; Zhang, Chunbo; Tomlinson, Brian; Wong, Gary Wing Kin; Tan, Hui Jan; Ali, Raymond Azman; Mohamed, Zahurin; Kwan, Patrick.

In: Human Genetics, Vol. 133, No. 5, 2014, p. 651-659.

Research output: Contribution to journalArticle

Baum, L, Haerian, BS, Ng, HK, Wong, VCN, Ng, PW, Lui, CHT, Sin, NC, Zhang, C, Tomlinson, B, Wong, GWK, Tan, HJ, Ali, RA, Mohamed, Z & Kwan, P 2014, 'Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy', Human Genetics, vol. 133, no. 5, pp. 651-659. https://doi.org/10.1007/s00439-013-1405-1
Baum, Larry ; Haerian, Batoul Sadat ; Ng, Ho Keung ; Wong, Virginia C N ; Ng, Ping Wing ; Lui, Colin H T ; Sin, Ngai Chuen ; Zhang, Chunbo ; Tomlinson, Brian ; Wong, Gary Wing Kin ; Tan, Hui Jan ; Ali, Raymond Azman ; Mohamed, Zahurin ; Kwan, Patrick. / Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. In: Human Genetics. 2014 ; Vol. 133, No. 5. pp. 651-659.
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abstract = "High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 {\%} were idiopathic, 42 {\%} symptomatic, and 40 {\%} cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r 2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.",
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AU - Baum, Larry

AU - Haerian, Batoul Sadat

AU - Ng, Ho Keung

AU - Wong, Virginia C N

AU - Ng, Ping Wing

AU - Lui, Colin H T

AU - Sin, Ngai Chuen

AU - Zhang, Chunbo

AU - Tomlinson, Brian

AU - Wong, Gary Wing Kin

AU - Tan, Hui Jan

AU - Ali, Raymond Azman

AU - Mohamed, Zahurin

AU - Kwan, Patrick

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N2 - High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r 2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.

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