Variant GADL1 and response to lithium therapy in bipolar I disorder

N Engl J Med. 2014 Jan 9;370(2):119-28. doi: 10.1056/NEJMoa1212444. Epub 2013 Dec 25.

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.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimanic Agents / therapeutic use*
  • Asian Continental Ancestry Group
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / ethnology
  • Bipolar Disorder / genetics*
  • Carboxy-Lyases / genetics*
  • China
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Lithium / therapeutic use*
  • Maintenance Chemotherapy
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Young Adult

Substances

  • Antimanic Agents
  • Lithium
  • Carboxy-Lyases
  • GADL1 protein, human