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Variant GADL1 and response to lithium therapy in bipolar I disorder.

The New England journal of medicine (2013-12-27)
Chien-Hsiun Chen, Chau-Shoun Lee, Ming-Ta Michael Lee, Wen-Chen Ouyang, Chiao-Chicy Chen, Mian-Yoon Chong, Jer-Yuarn Wu, Happy Kuy-Lok Tan, Yi-Ching Lee, Liang-Jen Chuo, Nan-Ying Chiu, Hin-Yeung Tsang, Ta-Jen Chang, For-Wey Lung, Chen-Huan Chiu, Cheng-Ho Chang, Ying-Sheue Chen, Yuh-Ming Hou, Cheng-Chung Chen, Te-Jen Lai, Chun-Liang Tung, Chung-Ying Chen, Hsien-Yuan Lane, Tung-Ping Su, Jung Feng, Jin-Jia Lin, Ching-Jui Chang, Po-Ren Teng, Chia-Yih Liu, Chih-Ken Chen, I-Chao Liu, Jiahn-Jyh Chen, Ti Lu, Chun-Chieh Fan, Ching-Kuan Wu, Chang-Fang Li, Kathy Hsiao-Tsz Wang, Lawrence Shih-Hsin Wu, Hsin-Ling Peng, Chun-Ping Chang, Liang-Suei Lu, Yuan-Tsong Chen, Andrew Tai-Ann Cheng
ABSTRACT

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. 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. 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. Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

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