Alexander W Charney1, Eli A Stahl2, Elaine K Green3, Chia-Yen Chen4, Jennifer L Moran5, Kimberly Chambert6, Richard A Belliveau6, Liz Forty7, Katherine Gordon-Smith8, Phil H Lee9, Evelyn J Bromet10, Peter F Buckley11, Michael A Escamilla12, Ayman H Fanous13, Laura J Fochtmann10, Douglas S Lehrer14, Dolores Malaspina15, Stephen R Marder16, Christopher P Morley17, Humberto Nicolini18, Diana O Perkins19, Jeffrey J Rakofsky20, Mark H Rapaport20, Helena Medeiros21, Janet L Sobell22, Lena Backlund23, Sarah E Bergen24, Anders Juréus24, Martin Schalling25, Paul Lichtenstein24, James A Knowles26, Katherine E Burdick27, Ian Jones7, Lisa A Jones8, Christina M Hultman28, Roy Perlis29, Shaun M Purcell30, Steven A McCarroll31, Carlos N Pato21, Michele T Pato21, Ariana Di Florio32, Nick Craddock7, Mikael Landén33, Jordan W Smoller4, Douglas M Ruderfer34, Pamela Sklar35. 1. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neurosurgery, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, New York. Electronic address: alexander.charney@mssm.edu. 2. Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, New York. 3. School of Biomedical and Health Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Portland Square, Plymouth, UK. 4. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Boston, Massachusetts. 5. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts. 6. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts. 7. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. 8. Department of Psychiatry, University of Birmingham, Birmingham, UK. 9. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts. 10. Department of Psychiatry, Stony Brook University, Stony Brook, New York. 11. School of Medicine, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry, Georgia Regents University Medical Center, Augusta, Georgia. 12. Center of Excellence in Neuroscience, Department of Psychiatry, Texas Tech University Health Sciences Center at El Paso, El Paso, Texas. 13. Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, New York; Department of Psychiatry, VA New York Harbor Healthcare System, Brooklyn, New York. 14. Department of Psychiatry, Wright State University, Dayton, Ohio. 15. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, New York; Department of Psychiatry, New York University, New York, New York. 16. Semel Institute for Neuroscience, University of California, Los Angeles, California. 17. Department of Psychiatry and Behavioral Science, State University of New York, Upstate Medical University, Syracuse, New York; Department of Family Medicine, State University of New York, Upstate Medical University, Syracuse, New York; Department of Public Health and Preventive Medicine, State University of New York, Upstate Medical University, Syracuse, New York. 18. Center for Genomic Sciences, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico; Department of Psychiatry, Carracci Medical Group, Mexico City, Mexico. 19. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 20. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia. 21. Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, New York. 22. Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, California. 23. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 24. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 25. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 26. Department of Cell Biology, State University of New York, Downstate Medical Center, New York, New York. 27. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts; Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts. 28. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 29. Center for Experimental Therapeutics, Massachusetts General Hospital, Boston, Massachusetts. 30. Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts; Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts. 31. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department of Genetics, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts. 32. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. 33. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, Sahlgenska Academy at the Gothenburg University, Gothenburg, Sweden. 34. Division of Genetic Medicine, Departments of Medicine, Biomedical Informatics, and Psychiatry, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: douglas.ruderfer@vanderbilt.edu. 35. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, New York.
Abstract
BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
Authors: L Priebe; F A Degenhardt; S Herms; B Haenisch; M Mattheisen; V Nieratschker; M Weingarten; S Witt; R Breuer; T Paul; M Alblas; S Moebus; M Lathrop; M Leboyer; S Schreiber; M Grigoroiu-Serbanescu; W Maier; P Propping; M Rietschel; M M Nöthen; S Cichon; T W Mühleisen Journal: Mol Psychiatry Date: 2011-03-01 Impact factor: 15.992
Authors: T E Van Rheenen; K E Lewandowski; E J Tan; L H Ospina; D Ongur; E Neill; C Gurvich; C Pantelis; A K Malhotra; S L Rossell; K E Burdick Journal: Psychol Med Date: 2017-02-28 Impact factor: 7.723
Authors: E K Green; M Hamshere; L Forty; K Gordon-Smith; C Fraser; E Russell; D Grozeva; G Kirov; P Holmans; J L Moran; S Purcell; P Sklar; M J Owen; M C O'Donovan; L Jones; I R Jones; N Craddock Journal: Mol Psychiatry Date: 2012-10-16 Impact factor: 15.992
Authors: Detelina Grozeva; George Kirov; Dobril Ivanov; Ian R Jones; Lisa Jones; Elaine K Green; David M St Clair; Allan H Young; Nicol Ferrier; Anne E Farmer; Peter McGuffin; Peter A Holmans; Michael J Owen; Michael C O'Donovan; Nick Craddock Journal: Arch Gen Psychiatry Date: 2010-04
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Authors: Duncan S Palmer; Daniel P Howrigan; Sinéad B Chapman; Rolf Adolfsson; Nick Bass; Douglas Blackwood; Marco P M Boks; Chia-Yen Chen; Claire Churchhouse; Aiden P Corvin; Nicholas Craddock; David Curtis; Arianna Di Florio; Faith Dickerson; Nelson B Freimer; Fernando S Goes; Xiaoming Jia; Ian Jones; Lisa Jones; Lina Jonsson; Rene S Kahn; Mikael Landén; Adam E Locke; Andrew M McIntosh; Andrew McQuillin; Derek W Morris; Michael C O'Donovan; Roel A Ophoff; Michael J Owen; Nancy L Pedersen; Danielle Posthuma; Andreas Reif; Neil Risch; Catherine Schaefer; Laura Scott; Tarjinder Singh; Jordan W Smoller; Matthew Solomonson; David St Clair; Eli A Stahl; Annabel Vreeker; James T R Walters; Weiqing Wang; Nicholas A Watts; Robert Yolken; Peter P Zandi; Benjamin M Neale Journal: Nat Genet Date: 2022-04-11 Impact factor: 41.307
Authors: Roman Kotov; Katherine G Jonas; William T Carpenter; Michael N Dretsch; Nicholas R Eaton; Miriam K Forbes; Kelsie T Forbush; Kelsey Hobbs; Ulrich Reininghaus; Tim Slade; Susan C South; Matthew Sunderland; Monika A Waszczuk; Thomas A Widiger; Aidan G C Wright; David H Zald; Robert F Krueger; David Watson Journal: World Psychiatry Date: 2020-06 Impact factor: 49.548
Authors: Xiaoming Jia; Fernando S Goes; Adam E Locke; Duncan Palmer; Weiqing Wang; Sarah Cohen-Woods; Giulio Genovese; Anne U Jackson; Chen Jiang; Mark Kvale; Niamh Mullins; Hoang Nguyen; Mehdi Pirooznia; Margarita Rivera; Douglas M Ruderfer; Ling Shen; Khanh Thai; Matthew Zawistowski; Yongwen Zhuang; Gonçalo Abecasis; Huda Akil; Sarah Bergen; Margit Burmeister; Sinéad Chapman; Melissa DelaBastide; Anders Juréus; Hyun Min Kang; Pui-Yan Kwok; Jun Z Li; Shawn E Levy; Eric T Monson; Jennifer Moran; Janet Sobell; Stanley Watson; Virginia Willour; Sebastian Zöllner; Rolf Adolfsson; Douglas Blackwood; Michael Boehnke; Gerome Breen; Aiden Corvin; Nick Craddock; Arianna DiFlorio; Christina M Hultman; Mikael Landen; Cathryn Lewis; Steven A McCarroll; W Richard McCombie; Peter McGuffin; Andrew McIntosh; Andrew McQuillin; Derek Morris; Richard M Myers; Michael O'Donovan; Roel Ophoff; Marco Boks; Rene Kahn; Willem Ouwehand; Michael Owen; Carlos Pato; Michele Pato; Danielle Posthuma; James B Potash; Andreas Reif; Pamela Sklar; Jordan Smoller; Patrick F Sullivan; John Vincent; James Walters; Benjamin Neale; Shaun Purcell; Neil Risch; Catherine Schaefer; Eli A Stahl; Peter P Zandi; Laura J Scott Journal: Mol Psychiatry Date: 2021-01-22 Impact factor: 13.437