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

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

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  • N Engl J Med. 2014 May 8;370(19):1866.

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.).

PMID:
24369049
DOI:
10.1056/NEJMoa1212444
[Indexed for MEDLINE]
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