Summary

In this genome-wide association study in patients of Han Chinese descent with bipolar I disorder, two SNPs in glutamate decarboxylase-like protein 1 (GADL1) were found to have 93% sensitivity in predicting response to lithium. One of these response alleles occurs in roughly half of the Han Chinese population, suggesting that lithium may benefit half of patients with bipolar I disorder in Taiwan. The alleles are rare in European and African populations.

Design

• N=1,647 patients of Han Chinese descent with bipolar I disorder were genotyped. Of these, patients with good adherence to lithium for ≥2 years (n=294) were used in the genome-wide association study (discovery cohort).
• Genetic regions associated with response to lithium were identified, and replication tests were performed in 2 separate groups:
  • First replication cohort: n=100
  • Second replication cohort: n=24
• Setting: recruitment from outpatient clinics and inpatient units in the Taiwan Bipolar Consortium.
• Outcome measures: the Alda scale was used to classify response to lithium.

Results

• The strongest association was seen in two SNPs in the introns of the gene encoding glutamate decarboxylase-like protein 1 (GADL1), which is expressed in the brain, and may have a function similar to glutamate decarboxylase (GAD). Underexpression of GAD isoforms has been previously observed in patients with bipolar disorder.
• These two SNPs were 93% sensitive in predicting response to lithium.
• In the second replication cohort (n=24), 16 patients had the response alleles, and all 16 had a good response to lithium (Alda score of 8-10), while the 8 patients without the allele had a poor response (Alda score of 0-3).

Reference

Chen C-H, Lee C-S, Lee M-TM, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med. 2014;370(2):119-128. doi:10.1056/NEJMoa1212444.