Olav B Smeland1, Alexey Shadrin2, Shahram Bahrami2, Iris Broce3, Martin Tesli4, Oleksandr Frei2, Katrine V Wirgenes5, Kevin S O'Connell2, Florian Krull2, Francesco Bettella2, Nils Eiel Steen2, Leo Sugrue3, Yunpeng Wang6, Per Svenningsson7, Manu Sharma8, Lasse Pihlstrøm9, Mathias Toft9, Michael O'Donovan10, Srdjan Djurovic11, Rahul Desikan3, Anders M Dale12, Ole A Andreassen13. 1. NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: o.b.smeland@medisin.uio.no. 2. NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 3. Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California. 4. NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Mental Health, Norwegian Institute of Public Health, Oslo, Norway. 5. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 6. Centre for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway. 7. Clinical Neuroscience, Department of Neurology, Karolinska Institute, Stockholm, Sweden. 8. Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany. 9. Department of Neurology, Oslo University Hospital, Oslo, Norway. 10. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom. 11. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. 12. Department of Cognitive Science, University of California, San Diego, La Jolla, California; Department of Neuroscience, University of California, San Diego, La Jolla, California; Department of Radiology, University of California, San Diego, La Jolla, California; Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California. 13. NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: o.a.andreassen@medisin.uio.no.
Abstract
BACKGROUND: Parkinson's disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders. METHODS: We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci. RESULTS: We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type-specific expression profiles. CONCLUSIONS: Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.
BACKGROUND: Parkinson's disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders. METHODS: We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci. RESULTS: We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type-specific expression profiles. CONCLUSIONS: Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.
Authors: Olav B Smeland; Shahram Bahrami; Oleksandr Frei; Alexey Shadrin; Kevin O'Connell; Jeanne Savage; Kyoko Watanabe; Florian Krull; Francesco Bettella; Nils Eiel Steen; Torill Ueland; Danielle Posthuma; Srdjan Djurovic; Anders M Dale; Ole A Andreassen Journal: Mol Psychiatry Date: 2019-01-04 Impact factor: 15.992
Authors: Jochen Schmitt; Kristin Schwarz; Hansjörg Baurecht; Melanie Hotze; Regina Fölster-Holst; Elke Rodríguez; Young A E Lee; Andre Franke; Frauke Degenhardt; Wolfgang Lieb; Christian Gieger; Michael Kabesch; Markus M Nöthen; Alan D Irvine; W H Irwin McLean; Stefanie Deckert; Victoria Stephan; Peter Schwarz; Martin Aringer; Natalija Novak; Stephan Weidinger Journal: J Allergy Clin Immunol Date: 2015-08-04 Impact factor: 10.793
Authors: Ole A Andreassen; Srdjan Djurovic; Wesley K Thompson; Andrew J Schork; Kenneth S Kendler; Michael C O'Donovan; Dan Rujescu; Thomas Werge; Martijn van de Bunt; Andrew P Morris; Mark I McCarthy; J Cooper Roddey; Linda K McEvoy; Rahul S Desikan; Anders M Dale Journal: Am J Hum Genet Date: 2013-01-31 Impact factor: 11.025
Authors: Jakob Grove; Stephan Ripke; Thomas D Als; Manuel Mattheisen; Raymond K Walters; Hyejung Won; Jonatan Pallesen; Esben Agerbo; Ole A Andreassen; Richard Anney; Swapnil Awashti; Rich Belliveau; Francesco Bettella; Joseph D Buxbaum; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Felecia Cerrato; Kimberly Chambert; Jane H Christensen; Claire Churchhouse; Karin Dellenvall; Ditte Demontis; Silvia De Rubeis; Bernie Devlin; Srdjan Djurovic; Ashley L Dumont; Jacqueline I Goldstein; Christine S Hansen; Mads Engel Hauberg; Mads V Hollegaard; Sigrun Hope; Daniel P Howrigan; Hailiang Huang; Christina M Hultman; Lambertus Klei; Julian Maller; Joanna Martin; Alicia R Martin; Jennifer L Moran; Mette Nyegaard; Terje Nærland; Duncan S Palmer; Aarno Palotie; Carsten Bøcker Pedersen; Marianne Giørtz Pedersen; Timothy dPoterba; Jesper Buchhave Poulsen; Beate St Pourcain; Per Qvist; Karola Rehnström; Abraham Reichenberg; Jennifer Reichert; Elise B Robinson; Kathryn Roeder; Panos Roussos; Evald Saemundsen; Sven Sandin; F Kyle Satterstrom; George Davey Smith; Hreinn Stefansson; Stacy Steinberg; Christine R Stevens; Patrick F Sullivan; Patrick Turley; G Bragi Walters; Xinyi Xu; Kari Stefansson; Daniel H Geschwind; Merete Nordentoft; David M Hougaard; Thomas Werge; Ole Mors; Preben Bo Mortensen; Benjamin M Neale; Mark J Daly; Anders D Børglum Journal: Nat Genet Date: 2019-02-25 Impact factor: 38.330
Authors: Rosalind A Eeles; Ali Amin Al Olama; Sara Benlloch; Edward J Saunders; Daniel A Leongamornlert; Malgorzata Tymrakiewicz; Maya Ghoussaini; Craig Luccarini; Joe Dennis; Sarah Jugurnauth-Little; Tokhir Dadaev; David E Neal; Freddie C Hamdy; Jenny L Donovan; Ken Muir; Graham G Giles; Gianluca Severi; Fredrik Wiklund; Henrik Gronberg; Christopher A Haiman; Fredrick Schumacher; Brian E Henderson; Loic Le Marchand; Sara Lindstrom; Peter Kraft; David J Hunter; Susan Gapstur; Stephen J Chanock; Sonja I Berndt; Demetrius Albanes; Gerald Andriole; Johanna Schleutker; Maren Weischer; Federico Canzian; Elio Riboli; Tim J Key; Ruth C Travis; Daniele Campa; Sue A Ingles; Esther M John; Richard B Hayes; Paul D P Pharoah; Nora Pashayan; Kay-Tee Khaw; Janet L Stanford; Elaine A Ostrander; Lisa B Signorello; Stephen N Thibodeau; Dan Schaid; Christiane Maier; Walther Vogel; Adam S Kibel; Cezary Cybulski; Jan Lubinski; Lisa Cannon-Albright; Hermann Brenner; Jong Y Park; Radka Kaneva; Jyotsna Batra; Amanda B Spurdle; Judith A Clements; Manuel R Teixeira; Ed Dicks; Andrew Lee; Alison M Dunning; Caroline Baynes; Don Conroy; Melanie J Maranian; Shahana Ahmed; Koveela Govindasami; Michelle Guy; Rosemary A Wilkinson; Emma J Sawyer; Angela Morgan; David P Dearnaley; Alan Horwich; Robert A Huddart; Vincent S Khoo; Christopher C Parker; Nicholas J Van As; Christopher J Woodhouse; Alan Thompson; Tim Dudderidge; Chris Ogden; Colin S Cooper; Artitaya Lophatananon; Angela Cox; Melissa C Southey; John L Hopper; Dallas R English; Markus Aly; Jan Adolfsson; Jiangfeng Xu; Siqun L Zheng; Meredith Yeager; Rudolf Kaaks; W Ryan Diver; Mia M Gaudet; Mariana C Stern; Roman Corral; Amit D Joshi; Ahva Shahabi; Tiina Wahlfors; Teuvo L J Tammela; Anssi Auvinen; Jarmo Virtamo; Peter Klarskov; Børge G Nordestgaard; M Andreas Røder; Sune F Nielsen; Stig E Bojesen; Afshan Siddiq; Liesel M Fitzgerald; Suzanne Kolb; Erika M Kwon; Danielle M Karyadi; William J Blot; Wei Zheng; Qiuyin Cai; Shannon K McDonnell; Antje E Rinckleb; Bettina Drake; Graham Colditz; Dominika Wokolorczyk; Robert A Stephenson; Craig Teerlink; Heiko Muller; Dietrich Rothenbacher; Thomas A Sellers; Hui-Yi Lin; Chavdar Slavov; Vanio Mitev; Felicity Lose; Srilakshmi Srinivasan; Sofia Maia; Paula Paulo; Ethan Lange; Kathleen A Cooney; Antonis C Antoniou; Daniel Vincent; François Bacot; Daniel C Tessier; Zsofia Kote-Jarai; Douglas F Easton Journal: Nat Genet Date: 2013-04 Impact factor: 38.330
Authors: Bernard Ng; Charles C White; Hans-Ulrich Klein; Solveig K Sieberts; Cristin McCabe; Ellis Patrick; Jishu Xu; Lei Yu; Chris Gaiteri; David A Bennett; Sara Mostafavi; Philip L De Jager Journal: Nat Neurosci Date: 2017-09-04 Impact factor: 24.884
Authors: Benjamin C Tendler; Karla L Miller; Chaoyue Wang; Aurea B Martins-Bach; Fidel Alfaro-Almagro; Gwenaëlle Douaud; Johannes C Klein; Alberto Llera; Cristiana Fiscone; Richard Bowtell; Lloyd T Elliott; Stephen M Smith Journal: Nat Neurosci Date: 2022-05-23 Impact factor: 28.771
Authors: Linn Rødevand; Shahram Bahrami; Oleksandr Frei; Yunhan Chu; Alexey Shadrin; Kevin S O'Connell; Olav B Smeland; Torbjørn Elvsåshagen; Guy F L Hindley; Srdjan Djurovic; Anders M Dale; Trine V Lagerberg; Nils Eiel Steen; Ole A Andreassen Journal: Transl Psychiatry Date: 2021-07-23 Impact factor: 6.222
Authors: Evelien Van Assche; Eva C Schulte; Ole A Andreassen; Olav B Smeland; Jurjen J Luykx Journal: Front Neurosci Date: 2022-02-09 Impact factor: 4.677
Authors: Robert C Wolf; Dusan Hirjak; Stefan Fritze; Anais Harneit; John L Waddington; Katharina M Kubera; Mike M Schmitgen; Marie-Luise Otte; Lena S Geiger; Heike Tost; Andreas Meyer-Lindenberg Journal: Eur Arch Psychiatry Clin Neurosci Date: 2021-05-05 Impact factor: 5.270
Authors: Shahram Bahrami; Guy Hindley; Bendik Slagsvold Winsvold; Kevin S O'Connell; Oleksandr Frei; Alexey Shadrin; Weiqiu Cheng; Francesco Bettella; Linn Rødevand; Ketil J Odegaard; Chun C Fan; Matti J Pirinen; Heidi M Hautakangas; Anders M Dale; Srdjan Djurovic; Olav B Smeland; Ole A Andreassen Journal: Brain Date: 2022-03-29 Impact factor: 13.501