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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
Amare, Azmeraw T; Thalamuthu, Anbupalam; Schubert, Klaus Oliver; Fullerton, Janice M; Ahmed, Muktar; Hartmann, Simon; Papiol, Sergi; Heilbronner, Urs; Degenhardt, Franziska; Tekola-Ayele, Fasil; Hou, Liping; Hsu, Yi-Hsiang; Shekhtman, Tatyana; Adli, Mazda; Akula, Nirmala; Akiyama, Kazufumi; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean-Michel; Hasler, Roland; Richard-Lepouriel, Hélène; Perroud, Nader; Backlund, Lena; Bhattacharjee, Abesh Kumar; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Biernacka, Joanna M; Birner, Armin; Marie-Claire, Cynthia; Cervantes, Pablo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Cruceanu, Cristiana; Czerski, Piotr M; Dalkner, Nina; Del Zompo, Maria; DePaulo, J Raymond; Étain, Bruno; Jamain, Stephane; Falkai, Peter; Forstner, Andreas J; Frisen, Louise; Frye, Mark A; Gard, Sébastien; Garnham, Julie S; Goes, Fernando S; Grigoroiu-Serbanescu, Maria; Fallgatter, Andreas J.
Afiliação
  • Amare AT; Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia. azmeraw.amare@adelaide.edu.au.
  • Thalamuthu A; Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, UNSW Medicine & Health, University of New South Wales, Sydney, Australia.
  • Schubert KO; Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
  • Fullerton JM; Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
  • Ahmed M; Neuroscience Research Australia, Sydney, NSW, Australia.
  • Hartmann S; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
  • Papiol S; Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
  • Heilbronner U; Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
  • Degenhardt F; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
  • Tekola-Ayele F; Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University Munich, Munich, Germany.
  • Hou L; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
  • Hsu YH; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Shekhtman T; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, LVR Klinikum Essen, University of Duisburg-Essen, Rheinische Kliniken, Essen, Germany.
  • Adli M; Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Akula N; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
  • Akiyama K; HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
  • Ardau R; Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
  • Arias B; Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
  • Aubry JM; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
  • Hasler R; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
  • Richard-Lepouriel H; Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
  • Perroud N; Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
  • Backlund L; Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
  • Bhattacharjee AK; Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
  • Bellivier F; Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
  • Benabarre A; Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
  • Bengesser S; Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
  • Biernacka JM; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
  • Birner A; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • Marie-Claire C; Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
  • Cervantes P; INSERM UMR-S 1144, Université Paris Cité, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
  • Chen HC; Bipolar and Depressive Disorders Program,, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
  • Chillotti C; Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
  • Cichon S; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • Cruceanu C; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
  • Czerski PM; Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
  • Dalkner N; INSERM UMR-S 1144, Université Paris Cité, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
  • Del Zompo M; Université Paris Cité, Inserm, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006, Paris, France.
  • DePaulo JR; The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
  • Étain B; Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
  • Jamain S; Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
  • Falkai P; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Forstner AJ; Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
  • Frisen L; Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
  • Frye MA; Douglas Mental Health University Institute, McGill University, Montreal, Canada.
  • Gard S; Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
  • Garnham JS; Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
  • Goes FS; Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
  • Grigoroiu-Serbanescu M; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
  • Fallgatter AJ; INSERM UMR-S 1144, Université Paris Cité, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
Mol Psychiatry ; 2023 Jul 11.
Article em En | MEDLINE | ID: mdl-37433967
ABSTRACT
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article