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Scalable mixed model methods for set-based association studies on large-scale categorical data analysis and its application to exome-sequencing data in UK Biobank
Affiliation:1. Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China;2. Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China;3. Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China;4. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA;5. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA;6. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA;7. Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China;8. Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China;9. Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China;10. NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China;11. Henan Key Lab of Biological Psychiatry, the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China;12. Chinese Institute for Brain Research, Beijing, China;13. Graduate School of Data Science, Seoul National University, Seoul, Korea;2. President, ASHG;3. Chief executive officer, ASHG;1. Department of Molecular Medicine, University of Pavia, Pavia, Italy;2. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;4. Texas Children’s Hospital, Houston, TX, USA;5. Molecular Diagnostics and Clinical Genetics Unit, Hospital Universitari Son Espases, Palma, Illes Balears, Spain;6. Genomics of Health, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain;7. Genetics Institute, Rambam Health Care Campus, Haifa, Israel;8. The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;9. AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France;10. Université de Paris, INSERM UMR-1141 Neurodiderot, Paris, France;11. Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland;12. Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey;13. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey;14. Department of Medical Biology, School of Medicine, Dokuz Eylul University, Izmir 35340, Turkey;15. The Genetic Institute, Emek Medical Center, Afula, Israel;16. Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy;17. Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy;18. Laboratory of Biochemistry-Biotechnology and Advanced Diagnostics, IRCCS Policlinico San Matteo Foundation, Pavia, Italy;19. Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy;20. Neuroradiology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy;21. Ophthalmology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy;22. Child Neurology and Psychiatry Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy;23. Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait;24. Tertiary ROP Center, Health Science University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey;25. Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey;26. Metabolic Pathologies and Pediatric Neurology Unit, Pediatric Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain;27. Pediatric Radiology Unit, Radiology Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain;28. Neurobiology, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain;29. Department of Radiology, Division of Pediatric Radiology, Dana Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel;30. Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel;31. AP-HM, Service de Génétique, Hôpital de la Timone, Marseille, France;32. Medical Genetics Service, CHUV, University of Lausanne, Lausanne, Switzerland;33. Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Pediatric Neurology, Malatya, Turkey;34. Department of Pediatric Neurology, School of Medicine, Dokuz Eylul University, Izmir 35340, Turkey;35. Department of Pediatrics B, Emek Medical Center, Afula, Israel;36. Poriya Medical Center and the Azrieli Faculty of Medicine, Bar-Ilan University, Ramat-Gan, Israel;37. Department of Biomedical Engineering, Tufts University, Medford, MA, USA;38. Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PY, UK;39. Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0PY, UK;40. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada;41. Brain and Mind Research Institute, University of Ottawa, Ottawa ON K1H 8L1, Canada;42. Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON K1H 8L1, Canada;43. University Children’s Hospital Zurich, University of Zurich, Zurich, Switzerland;44. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;45. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA;46. Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy;1. Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;2. Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA;3. Boston Dermatology and Laser Center, Massachusetts General Hospital, Boston, MA 02114, USA;4. Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA;5. Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA;6. Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA;7. Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA;8. Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University Cleveland, Cleveland, OH 44106, USA;9. Division of Hospital Medicine, Barnes Jewish Hospital, Washington University in St Louis, St. Louis, MO 63110, USA;10. Department of Neurology and Epileptology, Children’s Memorial Health Institute, Warsaw 04-736, Poland;11. Research Department, Children’s Memorial Health Institute, Warsaw 04-736, Poland;1. Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123, USA;2. Rady Children’s Hospital, San Diego, CA 92123, USA;3. Keck Graduate Institute, Claremont, CA 91711, USA;4. Illumina, Inc., San Diego, CA 92122, USA;5. Alexion, Astra Zeneca Rare Disease, Boston, MA 02210, USA;6. Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA;7. Fabric Genomics, Inc., Oakland, CA 94612, USA;8. Mass General Brigham, Broad Institute, Ariadne Labs and Harvard Medical School, Boston, MA 02115, USA;9. Genomenon, Inc., Ann Arbor, MI 48108, USA;10. TileDB, Inc., Cambridge, MA 02142, USA;11. Luna PBC, Inc., San Diego, CA 92121, USA;1. Hansjörg Wyss Department of Plastic Surgery, NYU Langone Medical Center, New York, NY, USA;2. GeneDx, Gaithersburg, MD, USA;3. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA;4. Division of Plastic and Reconstructive Surgery, University of Miami Hospital, Miami, FL, USA;5. Department of Pharmacology, Yale University, New Haven, CT, USA;6. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA;7. Division of Genetic Medicine, University of Washington, Seattle, WA, USA;8. Nemours Children’s Health, Wilmington, DE, USA;9. Department of Medical Genetics, University of Alberta, AB, Canada;10. Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA;11. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;12. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA;13. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA;14. Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA;15. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA;1. National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA;2. APHP.Nord, Robert Debré University Hospital, Department of Genetics, Paris, France;3. Université Paris Cité, Inserm UMR 1141, NeuroDiderot, 75019 Paris, France;4. Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, USA;5. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;7. Texas Children’s Hospital, Houston, TX, USA;8. Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan;9. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan;10. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;11. Department of Pediatrics, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands;12. United for Metabolic Diseases, Amsterdam, the Netherlands;13. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan;14. Department of Pediatrics, Shimada Ryoiku Medical Center Hachioji for Challenged Children, Tokyo, Japan;15. Amsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, the Netherlands;16. Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;17. Service de Neurologie Pédiatrique, DMU INOV-RDB, APHP, Hôpital Robert Debré, Paris, France;18. Department of Genetics, APHP-Robert Debré University Hospital, Paris, France;19. Laboratoire de biologie médicale multisites Seqoia - FMG2025, Paris, France;20. INSERM UMR1141, Neurodiderot, University of Paris, Paris, France;21. Service de Génétique Médicale, CHU Nantes, Nantes, France;22. Inserm, CNRS, University Nantes, l’institut du thorax, Nantes, France;23. APHP.Nord, Louis Mourier Hospital, Pediatrics Department, Paris, France;24. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;25. Medical Genetics Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy;26. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA;27. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;28. Department of Diagnostic Radiology and Imaging, Children’s National Hospital, Washington, DC, USA;29. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;30. Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Abstract:
Keywords:genome-wide association studies  GWAS  mixed model  categorical data analysis  whole-exome sequencing data analysis  UK Biobank  rare variants  proportional odds logistic mixed model  POLMM  family relatedness  gene-based analysis  region-based analysis
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