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

Amare AT 1 , Schubert KO 1 , Hou L 2 , Clark SR 1 , Papiol S 3 , Cearns M 1 Show all authors , Heilbronner U 3 , Degenhardt F 4 , Tekola-Ayele F 5 , Hsu YH 6 , Shekhtman T 7 , Adli M 8 , Akula N 2 , Akiyama K 9 , Ardau R 10 , Arias B 11 , Aubry JM 12 , Backlund L 13 , Bhattacharjee AK 7 , Bellivier F 14 , Benabarre A 15 , Bengesser S 16 , Biernacka JM 17 , Birner A 16 , Brichant-Petitjean C 14 , Cervantes P 18 , Chen HC 19 , Chillotti C 10 , Cichon S 4 , Cruceanu C 20 , Czerski PM 21 , Dalkner N 16 , Dayer A 12 , Del Zompo M 22 , DePaulo JR 23 , Étain B 14 , Jamain S 24 , Falkai P 25 , Forstner AJ 4 , Frisen L 13 , Frye MA 26 , Fullerton JM 27 , Gard S 28 , Garnham JS 29 , Goes FS 23 , Grigoroiu-Serbanescu M 30 , Grof P 31 , Hashimoto R 32 , Hauser J 21 , Herms S 4 , Hoffmann P 4 , Hofmann A 4 , Jiménez E 15 , Kahn JP 33 , Kassem L 2 , Kuo PH 34 , Kato T 35 , Kelsoe JR 7 , Kittel-Schneider S 36 , Kliwicki S 37 , König B 38 , Kusumi I 39 , Laje G 2 , Landén M 40 , Lavebratt C 13 , Leboyer M 41 , Leckband SG 42 , Tortorella A 43 , Manchia M 44 , Martinsson L 45 , McCarthy MJ 7 , McElroy SL 46 , Colom F 47 , Mitjans M 11 , Mondimore FM 23 , Monteleone P 48 , Nievergelt CM 7 , Nöthen MM 4 , Novák T 49 , O'Donovan C 29 , Ozaki N 50 , Ösby U 51 , Pfennig A 52 , Potash JB 23 , Reif A 36 , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium , Reininghaus E 16 , Rouleau GA 53 , Rybakowski JK 37 , Schalling M 13 , Schofield PR 27 , Schweizer BW 23 , Severino G 22 , Shilling PD 7 , Shimoda K 54 , Simhandl C 55 , Slaney CM 29 , Squassina A 22 , Stamm T 8 , Stopkova P 49 , Maj M 56 , Turecki G 20 , Vieta E 15 , Veeh J 36 , Witt SH 57 , Wright A 58 , Zandi PP 59 , Mitchell PB 58 , Bauer M 52 , Alda M 29 , Rietschel M 57 , McMahon FJ 2 , Schulze TG 2 , Baune BT 60

Affiliations 

  • 1 Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia
  • 2 Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA
  • 3 Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany
  • 4 Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany
  • 5 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
  • 6 HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA
  • 7 Department of Psychiatry, University of California San Diego, San Diego, CA, USA
  • 8 Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
  • 9 Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
  • 10 Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy
  • 11 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
  • 12 Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland
  • 13 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  • 14 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
  • 15 Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
  • 16 Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria
  • 17 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
  • 18 The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada
  • 19 Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan
  • 20 Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
  • 21 Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland
  • 22 Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
  • 23 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
  • 24 Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France
  • 25 Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany
  • 26 Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
  • 27 Neuroscience Research Australia, Sydney, NSW, Australia
  • 28 Service de psychiatrie, Hôpital Charles Perrens, Bordeaux, France
  • 29 Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
  • 30 Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania
  • 31 Mood Disorders Center of Ottawa, Ottawa, ON, Canada
  • 32 Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan
  • 33 Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France
  • 34 Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
  • 35 Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan
  • 36 Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
  • 37 Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
  • 38 Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria
  • 39 Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  • 40 Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden
  • 41 Inserm U955, Translational Psychiatry laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France
  • 42 Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA
  • 43 Department of Psychiatry, University of Perugia, Perugia, Italy
  • 44 Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
  • 45 Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
  • 46 Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, OH, USA
  • 47 Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain
  • 48 Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
  • 49 National Institute of Mental Health, Klecany, Czech Republic
  • 50 Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • 51 Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
  • 52 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
  • 53 Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
  • 54 Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
  • 55 Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria
  • 56 Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy
  • 57 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
  • 58 School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia
  • 59 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
  • 60 Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany. [email protected]
Mol Psychiatry, 2021 Jun;26(6):2457-2470.
PMID: 32203155 DOI: 10.1038/s41380-020-0689-5

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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