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Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

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.

SUBMITTER: Hou L

PROVIDER: S-EPMC4814312 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

Hou Liping L Heilbronner Urs U Degenhardt Franziska F Adli Mazda M Akiyama Kazufumi K Akula Nirmala N Ardau Raffaella R Arias Bárbara B Backlund Lena L Banzato Claudio E M CEM Benabarre Antoni A Bengesser Susanne S Bhattacharjee Abesh Kumar AK Biernacka Joanna M JM Birner Armin A Brichant-Petitjean Clara C Bui Elise T ET Cervantes Pablo P Chen Guo-Bo GB Chen Hsi-Chung HC Chillotti Caterina C Cichon Sven S Clark Scott R SR Colom Francesc F Cousins David A DA Cruceanu Cristiana C Czerski Piotr M PM Dantas Clarissa R CR Dayer Alexandre A Étain Bruno B Falkai Peter P Forstner Andreas J AJ Frisén Louise L Fullerton Janice M JM Gard Sébastien S Garnham Julie S JS Goes Fernando S FS Grof Paul P Gruber Oliver O Hashimoto Ryota R Hauser Joanna J Herms Stefan S Hoffmann Per P Hofmann Andrea A Jamain Stephane S Jiménez Esther E Kahn Jean-Pierre JP Kassem Layla L Kittel-Schneider Sarah S Kliwicki Sebastian S König Barbara B Kusumi Ichiro I Lackner Nina N Laje Gonzalo G Landén Mikael M Lavebratt Catharina C Leboyer Marion M Leckband Susan G SG Jaramillo Carlos A López CAL MacQueen Glenda G Manchia Mirko M Martinsson Lina L Mattheisen Manuel M McCarthy Michael J MJ McElroy Susan L SL Mitjans Marina M Mondimore Francis M FM Monteleone Palmiero P Nievergelt Caroline M CM Nöthen Markus M MM Ösby Urban U Ozaki Norio N Perlis Roy H RH Pfennig Andrea A Reich-Erkelenz Daniela D Rouleau Guy A GA Schofield Peter R PR Schubert K Oliver KO Schweizer Barbara W BW Seemüller Florian F Severino Giovanni G Shekhtman Tatyana T Shilling Paul D PD Shimoda Kazutaka K Simhandl Christian C Slaney Claire M CM Smoller Jordan W JW Squassina Alessio A Stamm Thomas T Stopkova Pavla P Tighe Sarah K SK Tortorella Alfonso A Turecki Gustavo G Volkert Julia J Witt Stephanie S Wright Adam A Young L Trevor LT Zandi Peter P PP Potash James B JB DePaulo J Raymond JR Bauer Michael M Reininghaus Eva Z EZ Novák Tomas T Aubry Jean-Michel JM Maj Mario M Baune Bernhard T BT Mitchell Philip B PB Vieta Eduard E Frye Mark A MA Rybakowski Janusz K JK Kuo Po-Hsiu PH Kato Tadafumi T Grigoroiu-Serbanescu Maria M Reif Andreas A Del Zompo Maria M Bellivier Frank F Schalling Martin M Wray Naomi R NR Kelsoe John R JR Alda Martin M Rietschel Marcella M McMahon Francis J FJ Schulze Thomas G TG

Lancet (London, England) 20160122 10023

<h4>Background</h4>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.<h4>Methods</h4>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 c ...[more]

PMID: 26806518

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Project description:Importance:Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). Objectives:To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. Design, Setting, and Participants:A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36?989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. Main Outcomes and Measures:Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. Results:Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P?<?5?×?10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. Conclusions and Relevance:This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

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Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

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Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

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