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.).
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.).
Authors: Azmeraw T Amare; Klaus Oliver Schubert; Liping Hou; Scott R Clark; Sergi Papiol; Urs Heilbronner; Franziska Degenhardt; Fasil Tekola-Ayele; Yi-Hsiang Hsu; Tatyana Shekhtman; Mazda Adli; Nirmala Akula; Kazufumi Akiyama; Raffaella Ardau; Bárbara Arias; Jean-Michel Aubry; Lena Backlund; Abesh Kumar Bhattacharjee; Frank Bellivier; Antonio Benabarre; Susanne Bengesser; Joanna M Biernacka; Armin Birner; Clara Brichant-Petitjean; Pablo Cervantes; Hsi-Chung Chen; Caterina Chillotti; Sven Cichon; Cristiana Cruceanu; Piotr M Czerski; Nina Dalkner; Alexandre Dayer; Maria Del Zompo; J Raymond DePaulo; Bruno Étain; Peter Falkai; Andreas J Forstner; Louise Frisen; Mark A Frye; Janice M Fullerton; Sébastien Gard; Julie S Garnham; Fernando S Goes; Maria Grigoroiu-Serbanescu; Paul Grof; Ryota Hashimoto; Joanna Hauser; Stefan Herms; Per Hoffmann; Andrea Hofmann; Stephane Jamain; Esther Jiménez; Jean-Pierre Kahn; Layla Kassem; Po-Hsiu Kuo; Tadafumi Kato; John Kelsoe; Sarah Kittel-Schneider; Sebastian Kliwicki; Barbara König; Ichiro Kusumi; Gonzalo Laje; Mikael Landén; Catharina Lavebratt; Marion Leboyer; Susan G Leckband; Alfonso Tortorella; Mirko Manchia; Lina Martinsson; Michael J McCarthy; Susan McElroy; Francesc Colom; Marina Mitjans; Francis M Mondimore; Palmiero Monteleone; Caroline M Nievergelt; Markus M Nöthen; Tomas Novák; Claire O'Donovan; Norio Ozaki; Urban Ösby; Andrea Pfennig; James B Potash; Andreas Reif; Eva Reininghaus; Guy A Rouleau; Janusz K Rybakowski; Martin Schalling; Peter R Schofield; Barbara W Schweizer; Giovanni Severino; Paul D Shilling; Katzutaka Shimoda; Christian Simhandl; Claire M Slaney; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Mario Maj; Gustavo Turecki; Eduard Vieta; Julia Volkert; Stephanie Witt; Adam Wright; Peter P Zandi; Philip B Mitchell; Michael Bauer; Martin Alda; Marcella Rietschel; Francis J McMahon; Thomas G Schulze; Bernhard T Baune Journal: JAMA Psychiatry Date: 2018-01-01 Impact factor: 21.596