Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.

Journal: medRxiv : the preprint server for health sciences

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Affiliated Institutions:  Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany. Department of Mental Health and Neuroscience, Translational Neurogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Department of Psychiatry, Human Genetics, Yale University, New Haven, CT, USA. Department of Center for Genomic Medicine, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Psychiatry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. CIMUS (Center for Research in Molecular Medicine and Chronic Diseases), Genomics and Bioinformatics, University of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain. Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany. Department of Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada. Department of Psychiatry, Brain, University Medical Center Utrecht, Utrecht, The Netherlands. Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health,, Toronto, ON, Canada. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. Obsessive-Compulsive Disorder Institute, McLean Hospital, Belmont, MA, USA. Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada. Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy. Department of Heath Sciences, University of Milano, Milano, Italy. Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Psychiatry, Aarhus, Denmark. Department of Psychiatry and Behavioral Sciences, General Hospital Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Departments of Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Department of Child Study Center and Psychiatry, Yale University, New Haven, CT, USA. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Services, Region Stockholm , Stockholm, Sweden. Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway. Department of Child and Adolescent Mental Health, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain. Department of Psychiatry, Icahn School of Medicine At Mount Sinai, New York, NY, USA. Department of Psychiatry, Universidade De São Paulo, São Paulo, Brazil. Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia. Pharmacogenetics Department, Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico City, México. Department of Surgery, Duke, Durham, NC, USA. Department of Psychiatry, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA. Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Genomics and Bioinformatics Group, University of Santiago de Compostela, Santiago de Compostela, Spain. Programa MIND Escoles, Hospital Sant Joan de Déu , Esplugues de Llobregat, Barcelona, Spain. Department of Psychiatry, Ospedale San Raffaele, Milano, Italy. Department of Psychiatry, University of Illinois Chicago, Chicago, IL, USA. Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore , MD, USA. Child and Adolesccent Psycchiatry Department, APHP, Paris, France. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. Psychiatry, McLean Hospital OCDI, Harvard Medical School, Belmont, MA, USA. qGenomics (Quantitative Genomics Laboratories), Esplugues de Llobregat, Barcelona, Spain. Department of Medical Epidemiology and Biostatistics, Center for Eating Disorders Innovation, Karolinska Institutet, Stockholm, Sweden. andMe, Inc., Sunnyvale, CA, USA. Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA. Department of Psychiatry and Behavioral Sciences, Child & Adolescent Psychiatry, Johns Hopkins University, Baltimore, MD, USA. Department of Biomedicine, Aarhus University, Aarhus, Denmark. Genetic Epidemiology Research Branch, National Institute of Mental Health, Bethesda, MD, USA. Department of Biomedicine, University of Bergen, Bergen, Norway. Department of Psychiatry, Møre og Romsdal Hospital Trust, Molde, Norway. Million Veteran Program (MVP) Coordinating Center, VA Boston Healthcare System, Boston, MA, USA. PsychGen Centre for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway. Department of Clinical Science, University of Bergen, Bergen, Norway. Department of Psychiatry, University of São Paulo, São Paulo, Brazil. Department of Medicine, Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, USA. Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA. Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. Department of Biostatistics, T.H. Chan School of Public Health, Boston, MA, USA. Research Department, Grupo Medico Carracci, Mexico City, Mexico. Department of Psychiatry, Yale University, West Haven, CT, USA. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Department of Psychiatry, University of California, Irvine (UCI), Irvine, CA, USA. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. COBRE Center for Neuromodulation, Butler Hospital, Providence, RI, USA. Department of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Providence, RI, USA. Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. Department of Psychiatry, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. Department of Psychiatry and Behavioral Science, Johns Hopkins University, Baltimore, MD, USA. Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, University of California, Los Angeles, Los Angeles, CA, USA. Department of Clinical Medicine, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Institute for Molecular Medicine Finland - FIMM, University of Helsinki, Helsinki, Finland. Department of Clinical Neuroscience and Neurorehabilitation, Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy. Department of Genetics, microbiology and statistics, IBUB, Universitat de Barcelona, Barcelona, Spain. Department of Psychiatry and Psychotherapy, Division of Neurogenetics and Molecular Psychiatry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Department of Mental disorders, Norwegian Institute of Public Health, New York, NY, USA. Department of Psychiatry and Behavioral Sciences, Child and Adolescent, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany. Department of Psychiatry, Child and Adolescent Psychiatry Unit (UPIA), Federal University of São Paulo (UNIFESP), São Paulo, Brazil. Department of Neurosciences and Mental Health, Medical School, Federal University of Bahia, Salvador, Brazil. Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Freiburg, Medical Center - University of Freiburg, Freiburg, Germany. Department of Public Health and Nursing, HUNT Center for Molecular and Clinical Epidemiology, Trondheim, Norway. Department of Psychiatry, Faculty of Medicine, Locaion Vumc, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Department of Psychiatry, Universidade de Sao Paulo, São Paulo, Brazil. OCD Institute, Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA. Department of Psychiatry, Division of Child and Adolescent Psychiatry, Columbia University, New York, NY, USA. Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Laboratory of Clinical Science, NIMH Intramural Research Program, Bethesda, MD, USA. Department of Computional Biology, Institute of Life Science, Fudan University, Fudan, China. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA. Department of Psychiatry, OCD Clinical and Research Unit, Bellvitge Hospital, Barcelona, Spain. Psychosomatic Department, Windach Hospital of Neurobehavioural Research and Therapy, Windach, Germany. Department of Psychiatry, Washington U. School of Medicine, St Louis, MO, USA. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Departments of Rijksuniversiteit Groningen and Psychiatry, University Medical Center Groninge, Groningen, The Netherlands. Department of Psychiatry, Institute of The Royal Netherlands Academy of Arts and Sciences (NIN-KNAW), Amsterdam, The Netherlands. Discipline of Psychiatry and Mental Health, School of Clinical Medicine, UNSW, Sydney, NSW, Australia. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany. Child Study Center and Psychiatry, Yale School of Medicine, New Haven, CT, USA. Department of Psychiatry, New York State Psychiatric Institute, New York, NY, USA. Department of Medicine, VA Boston Healthcare System, Boston, MA, USA. Department of Psychiatry, Child Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry & Psychotherapy, University Medicine Greifswald, Greifswald, Germany. COBRE Center on Neuromodulation, Butler Hospital, Providence, RI, USA. Department of Psychiatry, Child and Adolescent Psychiatry, University of Michigan, Ann Arbor, MI, USA. Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. Bergen Center for brain plasticity, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway. Department of Addictology and Psychiatry, Univ Paris Est Créteil, AP-HP, Inserm, Paris, France. Department of Psychiatry, SA MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa. Department of Mental Health, Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Psychiatry, Carracci Medical Group, Mexico City, México. Mental Health Center Copenhagen, Copenhagen Research Center for Mental Health, Mental Health services in the Capital Region of Denmark, Copenhagen, Denmark. Department of Psychiatry, Rutgers University, Piscataway, NJ, USA. Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Department of Psychiatry and Biobehavioral Sciences, Child and Adolescent Psychiatry, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA. Department of Psychiatry, Yale University, New Haven, CT, USA. Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Amsterdam, The Netherlands. Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Department of Psychiatry and Behavioral Neurosciences, Child and Adolescent Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Dept of Psychiatry & Neuroscience Institute, SAMRC Unit on Risk & Reslience in Mental Disorders, University of Cape Town, Cape Town, Western Cape, South Africa. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Department of Cardiology, University of Milan, Milan, Italy. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Mental Health Services (RHP), Copenhagen, Denmark. Institute of Clinical Medicine, NORMENT Centre, University of Oslo, Oslo, Norway. Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich (PUK), University of Zurich, Zürich, Switzerland. HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway. Bergen Center for Brain Plasticity (BCBP), Psychiatry, Haukeland University Hospital, Bergen, Norway. Department of Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Psychosis Reasearch Unit, Aarhus University Hospital - Psychiatry, Aarhus N, Denmark. Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway. Bergen Center for Brain Plasticity, Psychiatry, Haukeland University Hospital, Bergen, Norway. Department of Psychiatry, University of Freiburg - Medical Faculty, Freiburg, Germany. Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich (PUK), University of Zurich, Zürich, Schweiz. Departments of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany. Department of Research and Innovation, Clinical Neuroscience, Oslo University Hospital and University of Oslo, Oslo, Norway. Social, Genetic, and Developmental Psychiatric Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland. Department of Psychiatry, The Mathison Centre for Mental Health Research & Education, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA. PsychGen Center for Genetic Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Department of Psychiatry, Amsterdam UMC location AMC, Amsterdam, The Netherlands. Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA. Department of Psychiatry, Human Genetics (Psychiatry), Yale University School of Medicine, West Haven, CT, USA. Psychiatry and Genetics Institute, Center for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA. Department of Mental Health and Neuroscience, QIMR Berghofer, Brisbane, Australia. Department of Community Health and Epidemiology and Faculty of Computer Science, Dalhousie University, Halifax, NS, Canada.

Abstract summary 

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting , , and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.

Authors & Co-authors:  Strom Nora I NI Gerring Zachary F ZF Galimberti Marco M Yu Dongmei D Halvorsen Matthew W MW Abdellaoui Abdel A Rodriguez-Fontenla Cristina C Sealock Julia M JM Bigdeli Tim T Coleman Jonathan R JR Mahjani Behrang B Thorp Jackson G JG Bey Katharina K Burton Christie L CL Luykx Jurjen J JJ Zai Gwyneth G Alemany Silvia S Andre Christine C Askland Kathleen D KD Banaj Nerisa N Barlassina Cristina C Nissen Judith Becker JB Bienvenu O Joseph OJ Black Donald D Bloch Michael H MH Boberg Julia J Børte Sigrid S Bosch Rosa R Breen Michael M Brennan Brian P BP Brentani Helena H Buxbaum Joseph D JD Bybjerg-Grauholm Jonas J Byrne Enda M EM Cabana-Dominguez Judit J Camarena Beatriz B Camarena Adrian A Cappi Carolina C Carracedo Angel A Casas Miguel M Cavallini Maria Cristina MC Ciullo Valentina V Cook Edwin H EH Crosby Jesse J Cullen Bernadette A BA De Schipper Elles J EJ Delorme Richard R Djurovic Srdjan S Elias Jason A JA Estivill Xavier X Falkenstein Martha J MJ Fundin Bengt T BT Garner Lauryn L German Chris C Gironda Christina C Goes Fernando S FS Grados Marco A MA Grove Jakob J Guo Wei W Haavik Jan J Hagen Kristen K Harrington Kelly K Havdahl Alexandra A Höffler Kira D KD Hounie Ana G AG Hucks Donald D Hultman Christina C Janecka Magdalena M Jenike Eric E Karlsson Elinor K EK Kelley Kara K Klawohn Julia J Krasnow Janice E JE Krebs Kristi K Lange Christoph C Lanzagorta Nuria N Levey Daniel D Lindblad-Toh Kerstin K Macciardi Fabio F Maher Brion B Mathes Brittany B McArthur Evonne E McGregor Nathaniel N McLaughlin Nicole C NC Meier Sandra S Miguel Euripedes C EC Mulhern Maureen M Nestadt Paul S PS Nurmi Erika L EL O'Connell Kevin S KS Osiecki Lisa L Ousdal Olga Therese OT Palviainen Teemu T Pedersen Nancy L NL Piras Fabrizio F Piras Federica F Potluri Sriramya S Rabionet Raquel R Ramirez Alfredo A Rauch Scott S Reichenberg Abraham A Riddle Mark A MA Ripke Stephan S Rosário Maria C MC Sampaio Aline S AS Schiele Miriam A MA Skogholt Anne Heidi AH Sloofman Laura G Sloofman G LGSG Smit Jan J Soler Artigas María AM Thomas Laurent F LF Tifft Eric E Vallada Homero H van Kirk Nathanial N Veenstra-VanderWeele Jeremy J Vulink Nienke N NN Walker Christopher P CP Wang Ying Y Wendland Jens R JR Winsvold Bendik S BS Yao Yin Y Zhou Hang H Agrawal Arpana A Alonso Pino P Berberich Götz G Bucholz Kathleen K KK Bulik Cynthia M CM Cath Danielle D Denys Damiaan D Eapen Valsamma V Edenberg Howard H Falkai Peter P Fernandez Thomas V TV Fyer Abby J AJ Gaziano J M JM Geller Dan A DA Grabe Hans J HJ Greenberg Benjamin D BD Hanna Gregory L GL Hickie Ian B IB Hougaard David M DM Kathmann Norbert N Kennedy James J Lai Dongbing D Landén Mikael M Le Hellard Stéphanie S Leboyer Marion M Lochner Christine C McCracken James T JT Medland Sarah E SE Mortensen Preben B PB Neale Benjamin M BM Nicolini Humberto H Nordentoft Merete M Pato Michele M Pato Carlos C Pauls David L DL Piacentini John J Pittenger Christopher C Posthuma Danielle D Ramos-Quiroga Josep Antoni JA Rasmussen Steven A SA Richter Margaret A MA Rosenberg David R DR Ruhrmann Stephan S Samuels Jack F JF Sandin Sven S Sandor Paul P Spalletta Gianfranco G Stein Dan J DJ Stewart S Evelyn SE Storch Eric A EA Stranger Barbara E BE Turiel Maurizio M Werge Thomas T Andreassen Ole A OA Børglum Anders D AD Walitza Susanne S Hveem Kristian K Hansen Bjarne K BK Rück Christian P CP Martin Nicholas G NG Milani Lili L Mors Ole O Reichborn-Kjennerud Ted T Ribasés Marta M Kvale Gerd G Mataix-Cols David D Domschke Katharina K Grünblatt Edna E Wagner Michael M Zwart John-Anker JA Breen Gerome G Nestadt Gerald G Kaprio Jaakko J Arnold Paul D PD Grice Dorothy E DE Knowles James A JA Ask Helga H Verweij Karin J KJ Davis Lea K LK Smit Dirk J DJ Crowley James J JJ Scharf Jeremiah M JM Stein Murray B MB Gelernter Joel J Mathews Carol A CA Derks Eske M EM Mattheisen Manuel M

Study Outcome 

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Citations :  Als T.D., Kurki M.I., Grove J. et al. Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses (2023). Nat Med 29, 1832–1844. 10.1038/s41591-023-02352-1
Authors :  214
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Doi : 2024.03.13.24304161
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Study Population
Male,Female
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Publication Country
United States