Variant GADL1 and response to lithium therapy in bipolar I disorder

C. H. Chen, C. S. Lee, M. T M Lee, W. C. Ouyang, Chiao Chicy Chen, M. Y. Chong, J. Y. Wu, H. K L Tan, Y. C. Lee, L. J. Chuo, N. Y. Chiu, H. Y. Tsang, T. J. Chang, F. W. Lung, C. H. Chiu, C. H. Chang, Y. S. Chen, Y. M. Hou, Cheng Chung Chen, T. J. LaiC. L. Tung, C. Y. Chen, H. Y. Lane, T. P. Su, J. Feng, J. J. Lin, C. J. Chang, P. R. Teng, C. Y. Liu, C. K. Chen, I. C. Liu, J. J. Chen, T. Lu, C. C. Fan, C. K. Wu, C. F. Li, K. H T Wang, L. S H Wu, H. L. Peng, C. P. Chang, L. S. Lu, Y. T. Chen, A. T A Cheng

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P = 5.50×10-37 and P = 2.52×10-37, respectively) and in the replication sample of 100 patients (P = 9.19×10-15 for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent.

Original languageEnglish
Pages (from-to)119-128
Number of pages10
JournalNew England Journal of Medicine
Volume370
Issue number2
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Glutamate Decarboxylase
Bipolar Disorder
Lithium
Proteins
Single Nucleotide Polymorphism
Introns
Therapeutics
Linkage Disequilibrium
Exons
Taiwan
Genes
Depression
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chen, C. H., Lee, C. S., Lee, M. T. M., Ouyang, W. C., Chen, C. C., Chong, M. Y., ... Cheng, A. T. A. (2014). Variant GADL1 and response to lithium therapy in bipolar I disorder. New England Journal of Medicine, 370(2), 119-128. https://doi.org/10.1056/NEJMoa1212444

Variant GADL1 and response to lithium therapy in bipolar I disorder. / Chen, C. H.; Lee, C. S.; Lee, M. T M; Ouyang, W. C.; Chen, Chiao Chicy; Chong, M. Y.; Wu, J. Y.; Tan, H. K L; Lee, Y. C.; Chuo, L. J.; Chiu, N. Y.; Tsang, H. Y.; Chang, T. J.; Lung, F. W.; Chiu, C. H.; Chang, C. H.; Chen, Y. S.; Hou, Y. M.; Chen, Cheng Chung; Lai, T. J.; Tung, C. L.; Chen, C. Y.; Lane, H. Y.; Su, T. P.; Feng, J.; Lin, J. J.; Chang, C. J.; Teng, P. R.; Liu, C. Y.; Chen, C. K.; Liu, I. C.; Chen, J. J.; Lu, T.; Fan, C. C.; Wu, C. K.; Li, C. F.; Wang, K. H T; Wu, L. S H; Peng, H. L.; Chang, C. P.; Lu, L. S.; Chen, Y. T.; Cheng, A. T A.

In: New England Journal of Medicine, Vol. 370, No. 2, 2014, p. 119-128.

Research output: Contribution to journalArticle

Chen, CH, Lee, CS, Lee, MTM, Ouyang, WC, Chen, CC, Chong, MY, Wu, JY, Tan, HKL, Lee, YC, Chuo, LJ, Chiu, NY, Tsang, HY, Chang, TJ, Lung, FW, Chiu, CH, Chang, CH, Chen, YS, Hou, YM, Chen, CC, Lai, TJ, Tung, CL, Chen, CY, Lane, HY, Su, TP, Feng, J, Lin, JJ, Chang, CJ, Teng, PR, Liu, CY, Chen, CK, Liu, IC, Chen, JJ, Lu, T, Fan, CC, Wu, CK, Li, CF, Wang, KHT, Wu, LSH, Peng, HL, Chang, CP, Lu, LS, Chen, YT & Cheng, ATA 2014, 'Variant GADL1 and response to lithium therapy in bipolar I disorder', New England Journal of Medicine, vol. 370, no. 2, pp. 119-128. https://doi.org/10.1056/NEJMoa1212444
Chen, C. H. ; Lee, C. S. ; Lee, M. T M ; Ouyang, W. C. ; Chen, Chiao Chicy ; Chong, M. Y. ; Wu, J. Y. ; Tan, H. K L ; Lee, Y. C. ; Chuo, L. J. ; Chiu, N. Y. ; Tsang, H. Y. ; Chang, T. J. ; Lung, F. W. ; Chiu, C. H. ; Chang, C. H. ; Chen, Y. S. ; Hou, Y. M. ; Chen, Cheng Chung ; Lai, T. J. ; Tung, C. L. ; Chen, C. Y. ; Lane, H. Y. ; Su, T. P. ; Feng, J. ; Lin, J. J. ; Chang, C. J. ; Teng, P. R. ; Liu, C. Y. ; Chen, C. K. ; Liu, I. C. ; Chen, J. J. ; Lu, T. ; Fan, C. C. ; Wu, C. K. ; Li, C. F. ; Wang, K. H T ; Wu, L. S H ; Peng, H. L. ; Chang, C. P. ; Lu, L. S. ; Chen, Y. T. ; Cheng, A. T A. / Variant GADL1 and response to lithium therapy in bipolar I disorder. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 2. pp. 119-128.
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abstract = "BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P = 5.50×10-37 and P = 2.52×10-37, respectively) and in the replication sample of 100 patients (P = 9.19×10-15 for each SNP). These two SNPs had a sensitivity of 93{\%} for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent.",
author = "Chen, {C. H.} and Lee, {C. S.} and Lee, {M. T M} and Ouyang, {W. C.} and Chen, {Chiao Chicy} and Chong, {M. Y.} and Wu, {J. Y.} and Tan, {H. K L} and Lee, {Y. C.} and Chuo, {L. J.} and Chiu, {N. Y.} and Tsang, {H. Y.} and Chang, {T. J.} and Lung, {F. W.} and Chiu, {C. H.} and Chang, {C. H.} and Chen, {Y. S.} and Hou, {Y. M.} and Chen, {Cheng Chung} and Lai, {T. J.} and Tung, {C. L.} and Chen, {C. Y.} and Lane, {H. Y.} and Su, {T. P.} and J. Feng and Lin, {J. J.} and Chang, {C. J.} and Teng, {P. R.} and Liu, {C. Y.} and Chen, {C. K.} and Liu, {I. C.} and Chen, {J. J.} and T. Lu and Fan, {C. C.} and Wu, {C. K.} and Li, {C. F.} and Wang, {K. H T} and Wu, {L. S H} and Peng, {H. L.} and Chang, {C. P.} and Lu, {L. S.} and Chen, {Y. T.} and Cheng, {A. T A}",
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TY - JOUR

T1 - Variant GADL1 and response to lithium therapy in bipolar I disorder

AU - Chen, C. H.

AU - Lee, C. S.

AU - Lee, M. T M

AU - Ouyang, W. C.

AU - Chen, Chiao Chicy

AU - Chong, M. Y.

AU - Wu, J. Y.

AU - Tan, H. K L

AU - Lee, Y. C.

AU - Chuo, L. J.

AU - Chiu, N. Y.

AU - Tsang, H. Y.

AU - Chang, T. J.

AU - Lung, F. W.

AU - Chiu, C. H.

AU - Chang, C. H.

AU - Chen, Y. S.

AU - Hou, Y. M.

AU - Chen, Cheng Chung

AU - Lai, T. J.

AU - Tung, C. L.

AU - Chen, C. Y.

AU - Lane, H. Y.

AU - Su, T. P.

AU - Feng, J.

AU - Lin, J. J.

AU - Chang, C. J.

AU - Teng, P. R.

AU - Liu, C. Y.

AU - Chen, C. K.

AU - Liu, I. C.

AU - Chen, J. J.

AU - Lu, T.

AU - Fan, C. C.

AU - Wu, C. K.

AU - Li, C. F.

AU - Wang, K. H T

AU - Wu, L. S H

AU - Peng, H. L.

AU - Chang, C. P.

AU - Lu, L. S.

AU - Chen, Y. T.

AU - Cheng, A. T A

PY - 2014

Y1 - 2014

N2 - BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P = 5.50×10-37 and P = 2.52×10-37, respectively) and in the replication sample of 100 patients (P = 9.19×10-15 for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent.

AB - BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P = 5.50×10-37 and P = 2.52×10-37, respectively) and in the replication sample of 100 patients (P = 9.19×10-15 for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent.

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U2 - 10.1056/NEJMoa1212444

DO - 10.1056/NEJMoa1212444

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