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Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.
Hou, Liping; Heilbronner, Urs; Degenhardt, Franziska; Adli, Mazda; Akiyama, Kazufumi; Akula, Nirmala; Ardau, Raffaella; Arias, Bárbara; Backlund, Lena; Banzato, Claudio E M; Benabarre, Antoni; Bengesser, Susanne; Bhattacharjee, Abesh Kumar; Biernacka, Joanna M; Birner, Armin; Brichant-Petitjean, Clara; Bui, Elise T; Cervantes, Pablo; Chen, Guo-Bo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Clark, Scott R; Colom, Francesc; Cousins, David A; Cruceanu, Cristiana; Czerski, Piotr M; Dantas, Clarissa R; Dayer, Alexandre; Étain, Bruno; Falkai, Peter; Forstner, Andreas J; Frisén, Louise; Fullerton, Janice M; Gard, Sébastien; Garnham, Julie S; Goes, Fernando S; Grof, Paul; Gruber, Oliver; Hashimoto, Ryota; Hauser, Joanna; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Jamain, Stephane; Jiménez, Esther; Kahn, Jean-Pierre; Kassem, Layla; Kittel-Schneider, Sarah; Kliwicki, Sebastian.
Afiliação
  • Hou L; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
  • Heilbronner U; Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
  • Degenhardt F; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
  • Adli M; Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany; Fliedner Klinik Berlin, Center for Psychiatry, Psychotherapy and Psychosomatic Medicine, Berlin, Germany.
  • Akiyama K; Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
  • Akula N; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
  • Ardau R; Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
  • Arias B; Department of Biologia Animal, Unitat d'Antropologia (Dp Biología Animal), Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM, Barcelona, Catalonia, Spain.
  • Backlund L; Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • Banzato CEM; Department of Psychiatry, University of Campinas (Unicamp), Campinas, Brazil.
  • Benabarre A; Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
  • Bengesser S; Neurobiological Background and Anthropometrics in Bipolar Affective Disorder, Department of Psychiatry, Medical University of Graz, Graz, Austria.
  • Bhattacharjee AK; Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
  • Biernacka JM; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
  • Birner A; Neurobiological Background and Anthropometrics in Bipolar Affective Disorder, Department of Psychiatry, Medical University of Graz, Graz, Austria.
  • Brichant-Petitjean C; INSERM UMR-S 1144-Université Paris Diderot Pôle de Psychiatrie, AP-HP, Groupe Hospitalier Lariboisière-F Widal, Paris, France.
  • Bui ET; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
  • Cervantes P; The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
  • Chen GB; The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, QLD, Australia.
  • Chen HC; Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
  • Chillotti C; Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
  • Cichon S; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany; Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
  • Clark SR; Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
  • Colom F; Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
  • Cousins DA; Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
  • Cruceanu C; Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
  • Czerski PM; Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
  • Dantas CR; Department of Psychiatry, University of Campinas (Unicamp), Campinas, Brazil.
  • Dayer A; Department of Mental Health and Psychiatry, Mood Disorders Unit-Geneva University Hospitals, Geneva, Switzerland.
  • Étain B; Inserm U955, Psychiatrie Translationnelle, Créteil, France.
  • Falkai P; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
  • Forstner AJ; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
  • Frisén L; Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; C
  • Fullerton JM; Mental Illness Research Theme, Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
  • Gard S; Pôle de Psychiatrie Générale Universitaire, Centre Hospitalier Charles Perrens, Bordeaux, France.
  • Garnham JS; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, NS, Canada.
  • Goes FS; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
  • Grof P; Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
  • Gruber O; Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
  • Hashimoto R; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
  • Hauser J; Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
  • Herms S; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany; Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
  • Hoffmann P; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany; Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
  • Hofmann A; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
  • Jamain S; Inserm U955, Psychiatrie Translationnelle, Créteil, France.
  • Jiménez E; Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
  • Kahn JP; Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy-Laxou-Université de Lorraine, Nancy, France.
  • Kassem L; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
  • Kittel-Schneider S; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
  • Kliwicki S; Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Lancet ; 387(10023): 1085-1093, 2016 Mar 12.
Article em En | MEDLINE | ID: mdl-26806518
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtorno Bipolar / Compostos de Lítio / Polimorfismo de Nucleotídeo Único Tipo de estudo: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged Idioma: En Revista: Lancet Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtorno Bipolar / Compostos de Lítio / Polimorfismo de Nucleotídeo Único Tipo de estudo: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged Idioma: En Revista: Lancet Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos