Variations in the GADL1 gene predicted the response to lithium maintenance therapy among patients of Han Chinese ethnicity who have bipolar I disorder, according to a report published online Dec. 25 in the New England Journal of Medicine.
In a genomewide association study that was confirmed in two replication samples, the presence of two single-nucleotide polymorphisms (rs17026688 and rs17026651) located in the introns of the GADL1 gene had a 93% sensitivity and 85% specificity for predicting a positive treatment response, and a novel variant (IVS8+48delG) located in intron 8 of the GADL1 gene also predicted treatment response among bipolar patients of Han descent, said Chien-Hsiun Chen, Ph.D., of the Institute of Biomedical Sciences, Academia Sinica, Taipei (Taiwan) and his associates.
"These alleles are rare in persons of European or African ancestry, but it is possible that other variants in GADL1 may influence the response to lithium therapy in these populations," the researchers noted.
They assessed 1,647 Han Chinese patients with bipolar disorder I who were treated at Academia Sinica, psychiatric departments of general hospitals, or psychiatric institutions across Taiwan. The investigators identified 294 patients who had received lithium therapy and had demonstrated good adherence for at least 2 years. They proceeded to perform a discovery genomewide association study.
The median age of these 294 patients was 49 years, and 49% were men. During periods in which these participants were not receiving lithium, they had a median of six bipolar episodes (range, 4-144) since disease onset, at a median frequency of 1 per year (range, 0.4-15 per year).
The two single-nucleotide polymorphisms (SNPs) on a single chromosome of the GADL1 gene were strongly associated with a positive response to lithium; no other chromosomal region showed a significant association. This gene encodes glutamate decarboxylase–like protein 1.
The investigators then performed a replication study in a sample of 100 different patients with bipolar I disorder who had been treated with lithium and had demonstrated good adherence for at least 10 years. Again, genotyping of rs17026688 and rs17026651, along with flanking SNPs in the GADL1 gene, showed that only the two target SNPs had a sensitivity of 93% for predicting lithium response and a specificity of 85%-86%.
A final replication study was performed in 24 randomly selected patients who were followed for at least 2 years. All 16 participants who carried the SNPs had a good response to lithium maintenance therapy, and all 8 noncarriers had a poor lithium response, the investigators reported (New Engl. J. Med. 2013 Dec. 25 [doi: 10.1056/NEJMoa1212444]).
Dr. Chen and his associates then looked for other local variants likely to affect the expression of GADL1. They found a one-base deletion in intron 8 (IVS8+48delG), genotyped it in samples from all patients in the discovery and replication cohorts, and found that it was in complete linkage disequilibrium with rs17026688.
Although the precise physiologic function of the GADL1 protein is not yet known, it may be similar to that of the related protein glutamate decarboxylase. The latter protein is abnormally expressed in the brains of patients with bipolar disorder. "Our results are consistent with those of the first genomewide association study of lithium treatment, which suggests the importance of the glutamate pathway in bipolar disorder and the mechanism by which lithium may affect glutamatergic neurotransmission," Dr. Chen and his associates said.
"Nearly half of the 1,761 patients with bipolar I disorder in this study (47.2%) carry the response allele T of rs17026688, a prevalence similar to that in the general Han Chinese population, suggesting that approximately half of the patients with bipolar I disorder in Taiwan may benefit from lithium therapy," they noted.
Future research should assess whether these genetic variations can be used as biomarkers in affective disorders other than bipolar disorder, such as refractory major depressive disorder. Lithium often is used to augment the effects of antidepressants in MDD, the investigators added.
This study was funded by Academia Sinica and the National Science Council, Taiwan (National Center for Genomic Medicine, Translational Resource Center for Genomic Medicine, and National Research Program for Biopharmaceuticals).