Preben Bo Mortensen

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

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DOI

  • Azmeraw T Amare, South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
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  • Klaus Oliver Schubert, Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
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  • Liping Hou, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
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  • Scott R Clark, Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia.
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  • Sergi Papiol, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
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  • Micah Cearns, Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia.
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  • Urs Heilbronner, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
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  • Franziska Degenhardt, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Fasil Tekola-Ayele, Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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  • Yi-Hsiang Hsu, Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
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  • Tatyana Shekhtman, Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
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  • Mazda Adli, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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  • Nirmala Akula, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
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  • Kazufumi Akiyama, Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
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  • Raffaella Ardau, Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
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  • Bárbara Arias, 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.
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  • Jean-Michel Aubry, Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
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  • Lena Backlund, Unit of Computational Medicine, Center for Molecular Medicine, Karolinska University Hospital, L805, 171 76, Stockholm, Sweden.
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  • Abesh Kumar Bhattacharjee, Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
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  • Frank Bellivier, INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
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  • Antonio Benabarre, Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
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  • Susanne Bengesser, Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
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  • Joanna M Biernacka, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
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  • Armin Birner, Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
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  • Clara Brichant-Petitjean, INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
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  • Pablo Cervantes, The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
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  • Hsi-Chung Chen, Department of Psychiatry and Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
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  • Caterina Chillotti, Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
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  • Sven Cichon, Department of Biomedicine, Human Genomics Research Group, University Hospital and University of Basel, 4031, Basel, Switzerland.
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  • Cristiana Cruceanu, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
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  • Piotr M Czerski, Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
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  • Nina Dalkner, Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
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  • Alexandre Dayer, Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
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  • Maria Del Zompo, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Sardinia, Italy.
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  • J Raymond DePaulo, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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  • Bruno Étain, INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
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  • Stephane Jamain, Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France.
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  • Peter Falkai, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
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  • Andreas J Forstner, Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
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  • Louise Frisen, Unit of Computational Medicine, Center for Molecular Medicine, Karolinska University Hospital, L805, 171 76, Stockholm, Sweden.
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  • Mark A Frye, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
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  • Janice M Fullerton, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
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  • Sébastien Gard, Service de psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
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  • Julie S Garnham, Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada; Nova Scotia Health Authority, Halifax, NS, Canada.
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  • Fernando S Goes, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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  • Maria Grigoroiu-Serbanescu, Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest RO-041914, Romania.
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  • Paul Grof, 1] The International Group for the Study of Lithium-Treated Patients (IGSLI), Berlin, Germany [2] Mood Disorders Center of Ottawa, Ottawa, Ontario, Canada K1G 4G3 [3] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5T 1R8.
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  • Ryota Hashimoto, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
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  • Joanna Hauser, Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
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  • Stefan Herms, Department of Biomedicine, Human Genomics Research Group, University Hospital and University of Basel, 4031, Basel, Switzerland.
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  • Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

OriginalsprogEngelsk
TidsskriftMolecular Psychiatry
Antal sider14
ISSN1359-4184
DOI
StatusE-pub ahead of print - 16 mar. 2020

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