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Clinical Trial
. 2016 Mar 12;387(10023):1085-1093.
doi: 10.1016/S0140-6736(16)00143-4. Epub 2016 Jan 22.

Genetic Variants Associated With Response to Lithium Treatment in Bipolar Disorder: A Genome-Wide Association Study

Liping Hou  1 Urs Heilbronner  2 Franziska Degenhardt  3 Mazda Adli  4 Kazufumi Akiyama  5 Nirmala Akula  1 Raffaella Ardau  6 Bárbara Arias  7 Lena Backlund  8 Claudio E M Banzato  9 Antoni Benabarre  10 Susanne Bengesser  11 Abesh Kumar Bhattacharjee  12 Joanna M Biernacka  13 Armin Birner  11 Clara Brichant-Petitjean  14 Elise T Bui  1 Pablo Cervantes  15 Guo-Bo Chen  16 Hsi-Chung Chen  17 Caterina Chillotti  6 Sven Cichon  18 Scott R Clark  19 Francesc Colom  10 David A Cousins  20 Cristiana Cruceanu  21 Piotr M Czerski  22 Clarissa R Dantas  9 Alexandre Dayer  23 Bruno Étain  24 Peter Falkai  25 Andreas J Forstner  3 Louise Frisén  26 Janice M Fullerton  27 Sébastien Gard  28 Julie S Garnham  29 Fernando S Goes  30 Paul Grof  31 Oliver Gruber  32 Ryota Hashimoto  33 Joanna Hauser  22 Stefan Herms  18 Per Hoffmann  18 Andrea Hofmann  3 Stephane Jamain  24 Esther Jiménez  10 Jean-Pierre Kahn  34 Layla Kassem  1 Sarah Kittel-Schneider  35 Sebastian Kliwicki  36 Barbara König  37 Ichiro Kusumi  38 Nina Lackner  11 Gonzalo Laje  1 Mikael Landén  39 Catharina Lavebratt  8 Marion Leboyer  40 Susan G Leckband  41 Carlos A López Jaramillo  42 Glenda MacQueen  43 Mirko Manchia  44 Lina Martinsson  45 Manuel Mattheisen  46 Michael J McCarthy  47 Susan L McElroy  48 Marina Mitjans  7 Francis M Mondimore  30 Palmiero Monteleone  49 Caroline M Nievergelt  12 Markus M Nöthen  3 Urban Ösby  50 Norio Ozaki  51 Roy H Perlis  52 Andrea Pfennig  53 Daniela Reich-Erkelenz  54 Guy A Rouleau  55 Peter R Schofield  27 K Oliver Schubert  19 Barbara W Schweizer  30 Florian Seemüller  25 Giovanni Severino  56 Tatyana Shekhtman  57 Paul D Shilling  12 Kazutaka Shimoda  58 Christian Simhandl  59 Claire M Slaney  29 Jordan W Smoller  52 Alessio Squassina  56 Thomas Stamm  60 Pavla Stopkova  61 Sarah K Tighe  62 Alfonso Tortorella  63 Gustavo Turecki  21 Julia Volkert  35 Stephanie Witt  64 Adam Wright  65 L Trevor Young  66 Peter P Zandi  67 James B Potash  68 J Raymond DePaulo  30 Michael Bauer  53 Eva Z Reininghaus  11 Tomas Novák  61 Jean-Michel Aubry  23 Mario Maj  63 Bernhard T Baune  19 Philip B Mitchell  65 Eduard Vieta  10 Mark A Frye  69 Janusz K Rybakowski  36 Po-Hsiu Kuo  70 Tadafumi Kato  71 Maria Grigoroiu-Serbanescu  72 Andreas Reif  35 Maria Del Zompo  73 Frank Bellivier  14 Martin Schalling  8 Naomi R Wray  16 John R Kelsoe  57 Martin Alda  74 Marcella Rietschel  64 Francis J McMahon  75 Thomas G Schulze  76
Affiliations
Free PMC article
Clinical Trial

Genetic Variants Associated With Response to Lithium Treatment in Bipolar Disorder: A Genome-Wide Association Study

Liping Hou et al. Lancet. .
Free PMC article

Abstract

Background: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.

Methods: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.

Findings: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).

Interpretation: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.

Funding: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Trial registration: ClinicalTrials.gov NCT00001174.

Conflict of interest statement

Declaration of interests

Adli M has received a grant from Servier, speaker’s fees from Servier, Lundbecck, Aristo, Parexel, Gilead, ViiV, and Deutsche Bank plus a non-financial support from Lundbeck. Akiyama K has received speaker’s fees from Taisho Toyama Pharmaceutical. Alda M is funded by a grant of the Canadian Institutes of Health Research. Bauer M has received speaker’s fees from Alkermes, Astra Zeneca, BristolMyersSquibb, and Ferrer Internacional. Etain B received non-financial support from Labex Biopsy and Fondation Fondamental. Hashimoto R received grants and speaker honoraria from Dainippon Sumitomo Pharma and Novartis plus speaker honoraria from Eli Lilly Japan, GlaxoSmithKline, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharma, Pfizer, and the Yoshitomiyakuhin Corporation. Kato T received a grant from Takeda Pharmaceutical and fees from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka Pharmaceutical, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, Pfizer Japan, Mochida Pharmaceutical, Shionogi & Co, Janssen Pharmaceutical, Yoshitomiyakuhin Corporation, Agilent Technologies, Astellas Pharma, and Wako Pure Chemical Industries. Kusumi I received grants and fees from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis, Otsuka, Ono Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Shionogi, and Yoshitomi Pharmaceutical; he received grants from AbbVie GK, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, and Daiichi Sankyo and fees from Astellas Pharma and Janssen Pharmaceutical. McCarthy MJ served as unpaid consultant for Pathway Genomic (San Diego, USA). McElroy received a grant and fees from Naurex and Shire, further grants from Alkermes, Cephalon, Forest, Marriott Foundation, Orexigen Therapeutics, and Takeda Pharmaceutical, he further has served on the advisory boards for Bracket, Hoffmann-La Roche, MedAvante, Sunovion and received fees from Novo Nordisk. Perlis RH received personal fees from RID Ventures, Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus and Psybrain. Schofield PR received a grant from NHMRC. Schulze TG received a grant and fees from Roche Pharmaceuticals. Stamm TJ received personal fees from Servier, Lundbeck and BristolMyerSquibb. All above listed interests are outside of the submitted work. All other authors declare no conflict of interests.

Figures

Figure 1
Figure 1
Meta-analysis results of dichotomous and continuous lithium response phenotypes in all participants (CEU plus Asian samples). Genome-wide significant association can be detected with the continuous phenotype. SNPs in green are in linkage disequilibrium (r2>0·6) with the index SNPs (rs74795342).
Figure 2
Figure 2
Regional association plot of the region on chromosome 21 in which the genome-wide significant SNPs are located. Imputation quality for the top 4 SNPs was excellent (Table S3, Supplementary Materials).
Figure 3
Figure 3
Forest plots for the most significant SNP, rs74795342. [Panel A, dichotomous phenotype; Panel B, continuous phenotype].

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