title: Variant GADL1 and response to lithium therapy in bipolar I disorder.
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. (Funded by Academia Sinica and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Chien-Hsiun
authors.initials: CH
authors.lastname: Chen
authors.forename: Chau-Shoun
authors.initials: CS
authors.lastname: Lee
authors.forename: Ming-Ta Michael
authors.initials: MT
authors.lastname: Lee
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Ouyang
authors.forename: Chiao-Chicy
authors.initials: CC
authors.lastname: Chen
authors.forename: Mian-Yoon
authors.initials: MY
authors.lastname: Chong
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.forename: Happy Kuy-Lok
authors.initials: HK
authors.lastname: Tan
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lee
authors.forename: Liang-Jen
authors.initials: LJ
authors.lastname: Chuo
authors.forename: Nan-Ying
authors.initials: NY
authors.lastname: Chiu
authors.forename: Hin-Yeung
authors.initials: HY
authors.lastname: Tsang
authors.forename: Ta-Jen
authors.initials: TJ
authors.lastname: Chang
authors.forename: For-Wey
authors.initials: FW
authors.lastname: Lung
authors.forename: Chen-Huan
authors.initials: CH
authors.lastname: Chiu
authors.forename: Cheng-Ho
authors.initials: CH
authors.lastname: Chang
authors.forename: Ying-Sheue
authors.initials: YS
authors.lastname: Chen
authors.forename: Yuh-Ming
authors.initials: YM
authors.lastname: Hou
authors.forename: Cheng-Chung
authors.initials: CC
authors.lastname: Chen
authors.forename: Te-Jen
authors.initials: TJ
authors.lastname: Lai
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Tung
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Chen
authors.forename: Hsien-Yuan
authors.initials: HY
authors.lastname: Lane
authors.forename: Tung-Ping
authors.initials: TP
authors.lastname: Su
authors.forename: Jung
authors.initials: J
authors.lastname: Feng
authors.forename: Jin-Jia
authors.initials: JJ
authors.lastname: Lin
authors.forename: Ching-Jui
authors.initials: CJ
authors.lastname: Chang
authors.forename: Po-Ren
authors.initials: PR
authors.lastname: Teng
authors.forename: Chia-Yih
authors.initials: CY
authors.lastname: Liu
authors.forename: Chih-Ken
authors.initials: CK
authors.lastname: Chen
authors.forename: I-Chao
authors.initials: IC
authors.lastname: Liu
authors.forename: Jiahn-Jyh
authors.initials: JJ
authors.lastname: Chen
authors.forename: Ti
authors.initials: T
authors.lastname: Lu
authors.forename: Chun-Chieh
authors.initials: CC
authors.lastname: Fan
authors.forename: Ching-Kuan
authors.initials: CK
authors.lastname: Wu
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Li
authors.forename: Kathy Hsiao-Tsz
authors.initials: KH
authors.lastname: Wang
authors.forename: Lawrence Shih-Hsin
authors.initials: LS
authors.lastname: Wu
authors.forename: Hsin-Ling
authors.initials: HL
authors.lastname: Peng
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Chang
authors.forename: Liang-Suei
authors.initials: LS
authors.lastname: Lu
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Andrew Tai-Ann
authors.initials: AT
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018692:Antimanic Agents / Q000627:therapeutic use*; D044466:Asian People; D001714:Bipolar Disorder / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D002262:Carboxy-Lyases / Q000235:genetics*; D002681:China; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008094:Lithium / Q000627:therapeutic use*; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D008094:Lithium; D002262:Carboxy-Lyases; C585765:GADL1 protein, human