Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach

Micah Cearns¹, Azmeraw T Amare², Klaus Oliver Schubert³, Anbupalam Thalamuthu⁴, Joseph Frank⁵, Fabian Streit⁵, Mazda Adli⁶, Nirmala Akula⁷, Kazufumi Akiyama⁸, Raffaella Ardau⁹, Bárbara Arias¹⁰, Jean-Michel Aubry¹¹, Lena Backlund¹², Abesh Kumar Bhattacharjee¹³, Frank Bellivier¹⁴, Antonio Benabarre¹⁵, Susanne Bengesser¹⁶, Joanna M Biernacka¹⁷, Armin Birner¹⁶, Clara Brichant-Petitjean¹⁴, Pablo Cervantes¹⁸, Hsi-Chung Chen¹⁹, Caterina Chillotti⁹, Sven Cichon²⁰, Cristiana Cruceanu²¹, Piotr M Czerski²², Nina Dalkner¹⁶, Alexandre Dayer¹¹, Franziska Degenhardt²³, Maria Del Zompo²⁴, J Raymond DePaulo²⁵, Bruno Étain¹⁴, Peter Falkai²⁶, Andreas J Forstner²⁷, Louise Frisen¹², Mark A Frye²⁸, Janice M Fullerton²⁹, Sébastien Gard³⁰, Julie S Garnham³¹, Fernando S Goes²⁵, Maria Grigoroiu-Serbanescu³², Paul Grof³³, Ryota Hashimoto³⁴, Joanna Hauser²², Urs Heilbronner³⁵, Stefan Herms³⁶, Per Hoffmann³⁶, Andrea Hofmann²³, Liping Hou⁷, Yi-Hsiang Hsu³⁷, Stephane Jamain³⁸, Esther Jiménez¹⁵, Jean-Pierre Kahn³⁹, Layla Kassem⁷, Po-Hsiu Kuo⁴⁰, Tadafumi Kato⁴¹, John Kelsoe¹³, Sarah Kittel-Schneider⁴², Sebastian Kliwicki⁴³, Barbara König⁴⁴, Ichiro Kusumi⁴⁵, Gonzalo Laje⁷, Mikael Landén⁴⁶, Catharina Lavebratt¹², Marion Leboyer⁴⁷, Susan G Leckband⁴⁸, Mario Maj⁴⁹; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Mirko Manchia⁵⁰, Lina Martinsson⁵¹, Michael J McCarthy⁵², Susan McElroy⁵³, Francesc Colom⁵⁴, Marina Mitjans⁵⁴, Francis M Mondimore²⁵, Palmiero Monteleone⁵⁵, Caroline M Nievergelt¹³, Markus M Nöthen²³, Tomas Novák⁵⁶, Claire O'Donovan³¹, Norio Ozaki⁵⁷, Vincent Millischer⁵⁸, Sergi Papiol⁵⁹, Andrea Pfennig⁶⁰, Claudia Pisanu²⁴, James B Potash²⁵, Andreas Reif⁴², Eva Reininghaus¹⁶, Guy A Rouleau⁶¹, Janusz K Rybakowski⁴³, Martin Schalling¹², Peter R Schofield²⁹, Barbara W Schweizer²⁵, Giovanni Severino²⁴, Tatyana Shekhtman¹³, Paul D Shilling¹³, Katzutaka Shimoda⁶², Christian Simhandl⁶³, Claire M Slaney³¹, Alessio Squassina²⁴, Thomas Stamm⁶, Pavla Stopkova⁵⁶, Fasil Tekola-Ayele⁶⁴, Alfonso Tortorella⁶⁵, Gustavo Turecki²¹, Julia Veeh⁴², Eduard Vieta¹⁵, Stephanie H Witt⁵, Gloria Roberts⁶⁶, Peter P Zandi⁶⁷, Martin Alda³¹, Michael Bauer⁶⁰, Francis J McMahon⁷, Philip B Mitchell⁶⁶, Thomas G Schulze⁶⁸, Marcella Rietschel⁵, Scott R Clark¹, Bernhard T Baune⁶⁹

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Australia.
² South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Australia and Program for Quantitative Genomics, Harvard School of Public Health, USA.
³ Discipline of Psychiatry, School of Medicine, University of Adelaide, Australia and Northern Adelaide Local Health Network, Mental Health Services, Australia.
⁴ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Australia.
⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
⁶ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Germany.
⁷ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, USA.
⁸ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Japan.
⁹ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Italy.
¹⁰ 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, Spain.
¹¹ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Switzerland.
¹² Department of Molecular Medicine and Surgery, Karolinska Institute, Sweden and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹³ Department of Psychiatry, University of California San Diego, USA.
¹⁴ INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, France.
¹⁵ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain.
¹⁶ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Austria.
¹⁷ Department of Health Sciences Research, Mayo Clinic, USA and Department of Psychiatry and Psychology, Mayo Clinic, USA.
¹⁸ The Neuromodulation Unit, McGill University Health Centre, Canada.
¹⁹ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taiwan.
²⁰ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany; and Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Switzerland.
²¹ Douglas Mental Health University Institute, McGill University, Canada.
²² Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poland.
²³ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany.
²⁴ Department of Biomedical Sciences, University of Cagliari, Italy.
²⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, USA.
²⁶ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Germany.
²⁷ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany; Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Switzerland and Department of Psychiatry (UPK), University of Basel, Switzerland.
²⁸ Department of Psychiatry and Psychology, Mayo Clinic, USA.
²⁹ Neuroscience Research Australia, Australia and School of Medical Sciences, University of New South Wales, Australia.
³⁰ Service de Psychiatrie, Hôpital Charles Perrens, France.
³¹ Department of Psychiatry, Dalhousie University, Canada.
³² Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Romania.
³³ Mood Disorders Center of Ottawa, Canada.
³⁴ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Japan and Department of Psychiatry, Osaka University Graduate School of Medicine, Japan.
³⁵ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany and Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Germany.
³⁶ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany and Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Switzerland.
³⁷ Program for Quantitative Genomics, Harvard School of Public Health, USA and HSL Institute for Aging Research, Harvard Medical School, USA.
³⁸ Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, France.
³⁹ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, France.
⁴⁰ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taiwan.
⁴¹ Department of Psychiatry & Behavioral Science, Juntendo University, Graduate School of Medicine, Japan.
⁴² Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.
⁴³ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poland.
⁴⁴ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Austria.
⁴⁵ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Japan.
⁴⁶ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Sweden and Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
⁴⁷ Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, AP-HP, Mondor University Hospital, DMU Impact, Fondation FondaMental, France.
⁴⁸ Office of Mental Health, VA San Diego Healthcare System, USA.
⁴⁹ Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Italy; ,for a full list of Major Depressive Disorder Working Group of the PGC Investigators, see the Supplementary Material.
⁵⁰ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Italy and Department of Pharmacology, Dalhousie University, Canada.
⁵¹ Department of Clinical Neurosciences, Karolinska Institutet, Sweden.
⁵² Department of Psychiatry, University of California San Diego, USA and Department of Psychiatry, VA San Diego Healthcare System, USA.
⁵³ Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, USA.
⁵⁴ Mental Health Research Group, IMIM-Hospital del Mar, Spain and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
⁵⁵ Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Italy.
⁵⁶ National Institute of Mental Health, Czech Republic.
⁵⁷ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Japan.
⁵⁸ Department of Molecular Medicine and Surgery, Karolinska Institute, Sweden and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden and Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
⁵⁹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany and Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Germany.
⁶⁰ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Germany.
⁶¹ Montreal Neurological Institute and Hospital, McGill University, Canada.
⁶² Department of Psychiatry, Dokkyo Medical University School of Medicine, Japan.
⁶³ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Austria.
⁶⁴ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA.
⁶⁵ Department of Psychiatry, University of Perugia, Italy.
⁶⁶ School of Psychiatry, University of New South Wales, Australia.
⁶⁷ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, USA.
⁶⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, USA, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, USA; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany and Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Germany.
⁶⁹ Department of Psychiatry and Psychotherapy, University of Münster, Germany; Department of Psychiatry, Melbourne Medical School, University of Melbourne, Australia and The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia.

PMID: 35225756
DOI: 10.1192/bjp.2022.28

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach

Micah Cearns et al. Br J Psychiatry. 2022 Apr.

. 2022 Apr;220(4):219-228.

doi: 10.1192/bjp.2022.28. Epub 2022 Feb 28.

Authors

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Australia.
² South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Australia and Program for Quantitative Genomics, Harvard School of Public Health, USA.
³ Discipline of Psychiatry, School of Medicine, University of Adelaide, Australia and Northern Adelaide Local Health Network, Mental Health Services, Australia.
⁴ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Australia.
⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
⁶ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Germany.
⁷ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, USA.
⁸ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Japan.
⁹ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Italy.
¹⁰ 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, Spain.
¹¹ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Switzerland.
¹² Department of Molecular Medicine and Surgery, Karolinska Institute, Sweden and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹³ Department of Psychiatry, University of California San Diego, USA.
¹⁴ INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, France.
¹⁵ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain.
¹⁶ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Austria.
¹⁷ Department of Health Sciences Research, Mayo Clinic, USA and Department of Psychiatry and Psychology, Mayo Clinic, USA.
¹⁸ The Neuromodulation Unit, McGill University Health Centre, Canada.
¹⁹ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taiwan.
²⁰ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany; and Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Switzerland.
²¹ Douglas Mental Health University Institute, McGill University, Canada.
²² Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poland.
²³ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany.
²⁴ Department of Biomedical Sciences, University of Cagliari, Italy.
²⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, USA.
²⁶ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Germany.
²⁷ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany; Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Switzerland and Department of Psychiatry (UPK), University of Basel, Switzerland.
²⁸ Department of Psychiatry and Psychology, Mayo Clinic, USA.
²⁹ Neuroscience Research Australia, Australia and School of Medical Sciences, University of New South Wales, Australia.
³⁰ Service de Psychiatrie, Hôpital Charles Perrens, France.
³¹ Department of Psychiatry, Dalhousie University, Canada.
³² Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Romania.
³³ Mood Disorders Center of Ottawa, Canada.
³⁴ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Japan and Department of Psychiatry, Osaka University Graduate School of Medicine, Japan.
³⁵ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany and Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Germany.
³⁶ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Germany and Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Switzerland.
³⁷ Program for Quantitative Genomics, Harvard School of Public Health, USA and HSL Institute for Aging Research, Harvard Medical School, USA.
³⁸ Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, France.
³⁹ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, France.
⁴⁰ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taiwan.
⁴¹ Department of Psychiatry & Behavioral Science, Juntendo University, Graduate School of Medicine, Japan.
⁴² Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.
⁴³ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poland.
⁴⁴ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Austria.
⁴⁵ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Japan.
⁴⁶ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Sweden and Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
⁴⁷ Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, AP-HP, Mondor University Hospital, DMU Impact, Fondation FondaMental, France.
⁴⁸ Office of Mental Health, VA San Diego Healthcare System, USA.
⁴⁹ Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Italy; ,for a full list of Major Depressive Disorder Working Group of the PGC Investigators, see the Supplementary Material.
⁵⁰ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Italy and Department of Pharmacology, Dalhousie University, Canada.
⁵¹ Department of Clinical Neurosciences, Karolinska Institutet, Sweden.
⁵² Department of Psychiatry, University of California San Diego, USA and Department of Psychiatry, VA San Diego Healthcare System, USA.
⁵³ Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, USA.
⁵⁴ Mental Health Research Group, IMIM-Hospital del Mar, Spain and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
⁵⁵ Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Italy.
⁵⁶ National Institute of Mental Health, Czech Republic.
⁵⁷ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Japan.
⁵⁸ Department of Molecular Medicine and Surgery, Karolinska Institute, Sweden and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden and Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
⁵⁹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany and Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Germany.
⁶⁰ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Germany.
⁶¹ Montreal Neurological Institute and Hospital, McGill University, Canada.
⁶² Department of Psychiatry, Dokkyo Medical University School of Medicine, Japan.
⁶³ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Austria.
⁶⁴ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA.
⁶⁵ Department of Psychiatry, University of Perugia, Italy.
⁶⁶ School of Psychiatry, University of New South Wales, Australia.
⁶⁷ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, USA.
⁶⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, USA, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, USA; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany and Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Germany.
⁶⁹ Department of Psychiatry and Psychotherapy, University of Münster, Germany; Department of Psychiatry, Melbourne Medical School, University of Melbourne, Australia and The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia.

PMID: 35225756
DOI: 10.1192/bjp.2022.28

Erratum in

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach - CORRIGENDUM.
Cearns M, Amare AT, Schubert KO, Thalamuthu A, Frank J, Streit F, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry J, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Brichant-Petitjean C, Cervantes P, Chen H, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Dayer A, Degenhardt F, Zompo MD, DePaulo JR, Étain B, Falkai P, Forstner AJ, Frisen L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hofmann A, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe J, Kittel-Schneider S, Kliwicki S, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Manchia M, Martinsson L, McCarthy MJ, McElroy S, Colom F, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O'Donovan C, Ozaki N, Millischer V, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney … See abstract for full author list ➔ Cearns M, et al. Br J Psychiatry. 2022 Aug;221(2):494. doi: 10.1192/bjp.2022.55. Br J Psychiatry. 2022. PMID: 35505515 No abstract available.

Abstract

Background: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

Aims: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

Method: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi⁺Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

Results: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Conclusions: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Keywords: Mood stabilisers; bipolar affective disorders; depressive disorders; genetics; outcome studies.

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Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach

Affiliations

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach

Authors

Affiliations

Erratum in

Abstract

Grants and funding

LinkOut - more resources

Full Text Sources