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

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.).

Association Study of Gene Polymorphisms in GABA, Serotonin, Dopamine, and Alcohol Metabolism Pathways with Alcohol Dependence in Taiwanese Han Men.

BACKGROUND: The roles of GABA, serotonin, dopamine, and alcohol metabolism pathways in alcohol dependence (AD) are evident from animal models and human studies. Aims of this study were to investigate associations between genes in the 4 pathways and AD. METHODS: Male subjects from 2 independent samples of Taiwanese Han descent, a family sample of 179 trios and a case-control sample of 262 AD cases and 273 normal controls, were included in this study. The Schedules for Clinical Assessment in Neuropsychiatry was used for phenotype assessment of AD. We genotyped 282 single nucleotide polymorphisms (SNPs) located in 61 candidate genes involving alcohol metabolism, serotonin, and GABA systems among the family sample and replicated the top hits in the case-control sample. RESULTS: Fifteen SNPs located in 10 genes showed signals of associations (FBAT test p < 0.05) with AD in the family sample. Three SNPs, rs1229984 in ADH1B, rs671 in ALDH2, and rs2000292 in HTR1B, were significantly replicated in the case-control sample (p = 5.87 × 10(-14) , 5.12 × 10(-14) , and 0.0051, respectively). In the combined meta-analysis, these 3 SNPs and 1 additional SNP, rs698 in ADH1C, showed significant association after correcting for multiple comparisons, and rs1229984 and rs671 showed the strongest association (p < 10(-16) ). Logistic regression conditioning on rs1229984 and rs671 in the case-control sample showed that rs2000292 in HTR1B remained nominally significant. CONCLUSIONS: Genes in alcohol metabolism pathway, especially ADH1B and ALDH2, conferred the major genetic risk for AD in Taiwanese Han population. Some genes in GABA and serotonin pathways showed nominal association with AD.