Panagiotis Ferentinos1, Margarita Rivera2, Marcus Ising3, Sarah L Spain4, Sarah Cohen-Woods5, Amy W Butler6, Nicholas Craddock7, Michael J Owen7, Ania Korszun8, Lisa Jones9, Ian Jones7, Michael Gill10, John P Rice11, Wolfgang Maier12, Ole Mors13, Marcella Rietschel14, Susanne Lucae3, Elisabeth B Binder3, Martin Preisig15, Federica Tozzi16, Pierandrea Muglia17, Gerome Breen18, Ian W Craig19, Anne E Farmer19, Bertram Müller-Myhsok3, Peter McGuffin19, Cathryn M Lewis20. 1. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom. Electronic address: panagiotis.ferentinos@kcl.ac.uk. 2. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, University of Granada, Spain. 3. Max Planck Institute of Psychiatry, Munich, Germany. 4. Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom. 5. Department of Psychiatry, University of Adelaide, Adelaide, Australia. 6. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, China. 7. MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom. 8. Barts and The London Medical School, Queen Mary University of London, London, United Kingdom. 9. Department of Psychiatry, Neuropharmacology & Neurobiology Section, University of Birmingham, Birmingham, United Kingdom. 10. Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland. 11. Department of Psychiatry, Washington University, St. Louis, Missouri, United States. 12. Department of Psychiatry, University of Bonn, Bonn, Germany. 13. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark. 14. Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany. 15. University Hospital Center and University of Lausanne, Lausanne, Switzerland. 16. Aptuit Center for Drug Discovery & Development, Verona, Italy. 17. Department of Psychiatry, University of Toronto, Toronto, Canada. 18. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, United Kingdom. 19. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom. 20. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
Abstract
BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.
BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.
Authors: Min-Tzu Lo; Yunpeng Wang; Karolina Kauppi; Nilotpal Sanyal; Chun-Chieh Fan; Olav B Smeland; Andrew Schork; Dominic Holland; David A Hinds; Joyce Y Tung; Ole A Andreassen; Anders M Dale; Chi-Hua Chen Journal: Hum Mol Genet Date: 2017-11-15 Impact factor: 6.150
Authors: Katherine L Musliner; Preben B Mortensen; John J McGrath; Nis P Suppli; David M Hougaard; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Ole Andreassen; Carsten B Pedersen; Marianne G Pedersen; Ole Mors; Merete Nordentoft; Anders D Børglum; Thomas Werge; Esben Agerbo Journal: JAMA Psychiatry Date: 2019-05-01 Impact factor: 21.596
Authors: Marleen H M de Moor; Stéphanie M van den Berg; Karin J H Verweij; Robert F Krueger; Michelle Luciano; Alejandro Arias Vasquez; Lindsay K Matteson; Jaime Derringer; Tõnu Esko; Najaf Amin; Scott D Gordon; Narelle K Hansell; Amy B Hart; Ilkka Seppälä; Jennifer E Huffman; Bettina Konte; Jari Lahti; Minyoung Lee; Mike Miller; Teresa Nutile; Toshiko Tanaka; Alexander Teumer; Alexander Viktorin; Juho Wedenoja; Goncalo R Abecasis; Daniel E Adkins; Arpana Agrawal; Jüri Allik; Katja Appel; Timothy B Bigdeli; Fabio Busonero; Harry Campbell; Paul T Costa; George Davey Smith; Gail Davies; Harriet de Wit; Jun Ding; Barbara E Engelhardt; Johan G Eriksson; Iryna O Fedko; Luigi Ferrucci; Barbara Franke; Ina Giegling; Richard Grucza; Annette M Hartmann; Andrew C Heath; Kati Heinonen; Anjali K Henders; Georg Homuth; Jouke-Jan Hottenga; William G Iacono; Joost Janzing; Markus Jokela; Robert Karlsson; John P Kemp; Matthew G Kirkpatrick; Antti Latvala; Terho Lehtimäki; David C Liewald; Pamela A F Madden; Chiara Magri; Patrik K E Magnusson; Jonathan Marten; Andrea Maschio; Sarah E Medland; Evelin Mihailov; Yuri Milaneschi; Grant W Montgomery; Matthias Nauck; Klaasjan G Ouwens; Aarno Palotie; Erik Pettersson; Ozren Polasek; Yong Qian; Laura Pulkki-Råback; Olli T Raitakari; Anu Realo; Richard J Rose; Daniela Ruggiero; Carsten O Schmidt; Wendy S Slutske; Rossella Sorice; John M Starr; Beate St Pourcain; Angelina R Sutin; Nicholas J Timpson; Holly Trochet; Sita Vermeulen; Eero Vuoksimaa; Elisabeth Widen; Jasper Wouda; Margaret J Wright; Lina Zgaga; David Porteous; Alessandra Minelli; Abraham A Palmer; Dan Rujescu; Marina Ciullo; Caroline Hayward; Igor Rudan; Andres Metspalu; Jaakko Kaprio; Ian J Deary; Katri Räikkönen; James F Wilson; Liisa Keltikangas-Järvinen; Laura J Bierut; John M Hettema; Hans J Grabe; Cornelia M van Duijn; David M Evans; David Schlessinger; Nancy L Pedersen; Antonio Terracciano; Matt McGue; Brenda W J H Penninx; Nicholas G Martin; Dorret I Boomsma Journal: JAMA Psychiatry Date: 2015-07 Impact factor: 21.596
Authors: P Ferentinos; A Koukounari; R Power; M Rivera; R Uher; N Craddock; M J Owen; A Korszun; L Jones; I Jones; M Gill; J P Rice; M Ising; W Maier; O Mors; M Rietschel; M Preisig; E B Binder; K J Aitchison; J Mendlewicz; D Souery; J Hauser; N Henigsberg; G Breen; I W Craig; A E Farmer; B Müller-Myhsok; P McGuffin; C M Lewis Journal: Psychol Med Date: 2015-02-20 Impact factor: 7.723