Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes
Jo Knight,Jo Knight +1 more
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TLDR
For the first time, specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ are identified, providing an opportunity to understand the biology contributing to clinical differences of these disorders.Abstract:
Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.read more
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Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
Christian R. Marshall,Daniel P. Howrigan,Daniele Merico,Bhooma Thiruvahindrapuram,Wenting Wu,Douglas S. Greer,Danny Antaki,Aniket Shetty,Peter Holmans,Dalila Pinto,Madhusudan Gujral,William M. Brandler,Dheeraj Malhotra,Zhouzhi Wang,Karin V. Fuentes Fajarado,Michelle S. Maile,Stephan Ripke,Ingrid Agartz,Margot Albus,Madeline Alexander,Farooq Amin,Joshua R. Atkins,Silviu Alin Bacanu,Richard A. Belliveau,Sarah E. Bergen,Marcelo Ertalan,Elizabeth Bevilacqua,Tim B. Bigdeli,Donald W. Black,Richard Bruggeman,Nancy G. Buccola,Randy L. Buckner,Brendan Bulik-Sullivan,William Byerley,Wiepke Cahn,Guiqing Cai,Murray J. Cairns,Dominique Campion,Rita M. Cantor,Vaughan J. Carr,Noa Carrera,Stanley V. Catts,Kimberley D. Chambert,Wei Cheng,C. Robert Cloninger,David Cohen,Paul Cormican,Nicholas John Craddock,Benedicto Crespo-Facorro,James J. Crowley,David Curtis,Michael Davidson,Kenneth L. Davis,Franziska Degenhardt,Jurgen Del Favero,Lynn E. DeLisi,Dimitris Dikeos,Timothy G. Dinan,Srdjan Djurovic,Gary Donohoe,Elodie Drapeau,Jubao Duan,Frank Dudbridge,Peter Eichhammer,Johan G. Eriksson,Valentina Escott-Price,Laurent Essioux,Ayman H. Fanous,Kai-How Farh,Martilias S. Farrell,Josef Frank,Lude Franke,Robert B. Freedman,Nelson B. Freimer,Joseph I. Friedman,Andreas J. Forstner,Menachem Fromer,Giulio Genovese,Lyudmila Georgieva,Elliot S. Gershon,Ina Giegling,Paola Giusti-Rodríguez,Stephanie Godard,Jacqueline I. Goldstein,Jacob Gratten,Lieuwe de Haan,Marian L. Hamshere,Mark Hansen,Thomas Hansen,Vahram Haroutunian,Annette M. Hartmann,Frans Henskens,Stefan Herms,Joel N. Hirschhorn,Per Hoffinann,A. Hofman,Hailiang Huang,Masashi Ikeda,Inge Joa,Anna K. Kähler,René S. Kahn,Luba Kalaydjieva,Juha Karjalainen,David J. Kavanagh,Matthew C. Keller,Brian Kelly,James L. Kennedy,Yunjung Kim,James A. Knowles,Bettina Konte,Claudine Laurent,Phil Lee,S. Hong Lee,Sophie E. Legge,Bernard Lerer,Deborah L. Levy,Kung-Yee Liang,Jeffrey A. Lieberman,Jouko Lönnqvist,Carmel M. Loughland,Patrik K. E. Magnusson,Brion S. Maher,Wolfgang Maier,Jacques Mallet,Manuel Mattheisen,Morten Mattingsdal,Robert W. McCarley,Colm McDonald,Andrew M. McIntosh,Sandra Meier,Carin J. Meijer,Ingrid Melle,Raquelle I. Mesholam-Gately,Andres Metspalu,Patricia T. Michie,Lili Milani,Vihra Milanova,Younes Mokrab,Derek W. Morris,Bertram Müller-Myhsok,Kieran C. Murphy,Robin M. Murray,Inez Myin-Germeys,Igor Nenadic,Deborah A. Nertney,Gerald Nestadt,Kristin K. Nicodemus,Laura Nisenbaum,Annelie Nordin,Eadbhard O'Callaghan,Colm O'Dushlaine,Sang-Yun Oh,Ann Olincy,Line Olsen,F. Anthony O'Neill,Jim van Os,Christos Pantelis,George N. Papadimitriou,Elena Parkhomenko,Michele T. Pato,Tiina Paunio,Diana O. Perkins,Tune H. Pers,Olli Pietiläinen,Jonathan Pimm,Andrew Pocklington,John Powell,Alkes L. Price,Ann E. Pulver,Shaun Purcell,Digby Quested,Henrik B. Rasmussen,Abraham Reichenberg,Mark Reimers,Alexander Richards,Joshua L. Roffman,Panos Roussos,Douglas M. Ruderfer,Veikko Salomaa,Alan R. Sanders,Adam Savitz,Ulrich Schall,Thomas G. Schulze,Sibylle G. Schwab,Edward M. Scolnick,Rodney J. Scott,Larry J. Seidman,Jianxin Shi,Jeremy M. Silverman,Jordan W. Smoller,Erik Söderman,Chris C. A. Spencer,Eli A. Stahl,Eric Strengman,Jana Strohmaier,T. Scott Stroup,Jaana Suvisaari,Dragan M. Svrakic,Jin P. Szatkiewicz,Srinivas Thirumalai,Paul A. Tooney,Juha Veijola,Peter M. Visscher,John L. Waddington,Dermot Walsh,Bradley T. Webb,Mark Weiser,Dieter B. Wildenauer,Nigel Williams,Stephanie Williams,Stephanie H. Witt,Aaron R. Wolen,Brandon Wormley,Naomi R. Wray,Jing Qin Wu,Clement C. Zai,Rolf Adolfsson,Ole A. Andreassen,Douglas Blackwood,Elvira Bramon,Joseph D. Buxbaum,Sven Cichon,David A. Collier,Aiden Corvin,Mark J. Daly,Ariel Darvasi,Enrico Domenici,Tõnu Esko,Pablo V. Gejman,Michael Gill,Hugh Gurling,Christina M. Hultman,Nakao Iwata,Assen Jablensky,Erik G. Jönsson,Kenneth S. Kendler,George Kirov,Jo Knight,Douglas F. Levinson,Qingqin S. Li,Steven A. McCarroll,Andrew McQuillin,Jennifer L. Moran,Bryan J. Mowry,Markus M. Nöthen,Roel A. Ophoff,Michael John Owen,Aarno Palotie,Carlos N. Pato,Tracey L. Petryshen,Danielle Posthuma,Marcella Rietschel,Brien P. Riley,Dan Rujescu,Pamela Sklar,David St Clair,James T.R. Walters,Thomas Werge,Patrick F. Siillivan,Michael Conlon O'Donovan,Stephen W. Scherer,Benjamin M. Neale,Jonathan Sebat +262 more
TL;DR: A centralized analysis pipeline was applied to a SCZ cohort of 21,094 cases and 20,227 controls and Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia
Douglas M. Ruderfer,Ayman H. Fanous,Ayman H. Fanous,Ayman H. Fanous,Stephan Ripke,Stephan Ripke,Andrew McQuillin,Richard Amdur,Pablo V. Gejman,Michael Conlon O'Donovan,Ole A. Andreassen,Srdjan Djurovic,Christina M. Hultman,John R. Kelsoe,John R. Kelsoe,Stéphane Jamain,Stéphane Jamain,Mikael Landén,Mikael Landén,Marion Leboyer,Marion Leboyer,Vishwajit L. Nimgaonkar,John I. Nurnberger,Jordan W. Smoller,Nicholas John Craddock,Aiden Corvin,Patrick Sullivan,Peter Holmans,Pamela Sklar,Kenneth S. Kendler +29 more
TL;DR: In this paper, the authors performed a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases.
Journal ArticleDOI
Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia
Duncan S. Palmer,Daniel P. Howrigan,Sinéad B. Chapman,Rolf Adolfsson,Nicholas Bass,Douglas Blackwood,Marco P. Boks,Chia-Yen Chen,Claire Churchhouse,Aiden Corvin,Nicholas John Craddock,David Curtis,Arianna Di Florio,Faith Dickerson,Nelson B. Freimer,Fernando S. Goes,Xiaoming Jia,Ian Jones,Lisa Jones,Lina Jonsson,René S. Kahn,Mikael Landén,Adam E. Locke,Andrew M. McIntosh,Andrew McQuillin,Derek W. Morris,Michael Conlon O'Donovan,Roel A. Ophoff,Michael John Owen,Nancy L. Pedersen,Danielle Posthuma,Andreas Reif,Neil Risch,Catherine Schaefer,Laura J. 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,R.T Yolken,Peter P. Zandi,Benjamin M. Neale +46 more
TL;DR: In this article , the authors report results from the Bipolar exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder matched with 14,422 controls, finding an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes.
Journal ArticleDOI
Multi-ancestry eQTL meta-analysis of human brain identifies candidate causal variants for brain-related traits
TL;DR: A meta-analysis of 3,983 RNA-seq samples from 2,119 donors using the multivariate multiple QTL (mmQTL) approach characterizes the genetics of gene expression in the human brain and identifies candidate causal variants for brain-related traits as mentioned in this paper .
Journal ArticleDOI
Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci
Joseph D. Deak,Hang Zhou,Marco Galimberti,Daniel Levy,Frank R. Wendt,Sandra Sanchez-Roige,Alexander S. Hatoum,Emma C. Johnson,Yaira Z. Nunez,Ditte Demontis,Anders D. Børglum,Veera M. Rajagopal,Mariela V Jennings,Rachel L. Kember,Amy C. Justice,Howard J. Edenberg,Arpana Agrawal,Renato Polimanti,Henry R. Kranzler,Joel Gelernter +19 more
TL;DR: The authors performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs).
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TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Journal ArticleDOI
Biological insights from 108 schizophrenia-associated genetic loci
Stephan Ripke,Stephan Ripke,Benjamin M. Neale,Benjamin M. Neale,Aiden Corvin,James T.R. Walters,Kai-How Farh,Peter Holmans,Phil Lee,Phil Lee,Brendan Bulik-Sullivan,Brendan Bulik-Sullivan,David A. Collier,David A. Collier,Hailiang Huang,Hailiang Huang,Tune H. Pers,Tune H. Pers,Tune H. Pers,Ingrid Agartz,Ingrid Agartz,Esben Agerbo,Esben Agerbo,Margot Albus,Madeline Alexander,Farooq Amin,Silviu Alin Bacanu,Martin Begemann,Richard A. Belliveau,Judit Bene,Sarah E. Bergen,Sarah E. Bergen,Elizabeth Bevilacqua,Tim B. Bigdeli,Donald W. Black,Richard Bruggeman,Nancy G. Buccola,Randy L. Buckner,William Byerley,Wiepke Cahn,Guiqing Cai,Dominique Campion,Rita M. Cantor,Vaughan J. Carr,Noa Carrera,Stanley V. Catts,Kimberly Chambert,Raymond C.K. Chan,Ronald Y.L. Chen,Eric Y.H. Chen,Wei Cheng,Eric F.C. Cheung,Siow Ann Chong,C. Robert Cloninger,David Cohen,Nadine Cohen,Paul Cormican,Nicholas John Craddock,James J. Crowley,David Curtis,David Curtis,Michael Davidson,Kenneth L. Davis,Franziska Degenhardt,Jurgen Del Favero,Ditte Demontis,Ditte Demontis,Dimitris Dikeos,Timothy G. Dinan,Srdjan Djurovic,Gary Donohoe,Gary Donohoe,Elodie Drapeau,Jubao Duan,Frank Dudbridge,Naser Durmishi,Peter Eichhammer,Johan G. Eriksson,Johan G. Eriksson,Valentina Escott-Price,Laurent Essioux,Ayman H. Fanous,Martilias S. Farrell,Josef Frank,Lude Franke,Robert Freedman,Nelson B. Freimer,Marion Friedl,Joseph I. Friedman,Menachem Fromer,Menachem Fromer,Menachem Fromer,Giulio Genovese,Lyudmila Georgieva,Ina Giegling,Ina Giegling,Paola Giusti-Rodríguez,Stephanie Godard,Jacqueline I. Goldstein,Jacqueline I. Goldstein,Vera Golimbet,Srihari Gopal,Jacob Gratten,Lieuwe de Haan,Christian Hammer,Marian L. Hamshere,Mark Hansen,Thomas Hansen,Vahram Haroutunian,Vahram Haroutunian,Annette M. Hartmann,Frans Henskens,Stefan Herms,Stefan Herms,Joel N. Hirschhorn,Joel N. Hirschhorn,Per Hoffmann,Per Hoffmann,A. Hofman,Mads V. Hollegaard,David M. Hougaard,Masashi Ikeda,Inge Joa,Antonio Julià,René S. Kahn,Luba Kalaydjieva,Sena Karachanak-Yankova,Juha Karjalainen,David J. Kavanagh,Matthew C. Keller,James L. Kennedy,Andrey Khrunin,Yunjung Kim,Janis Klovins,James A. Knowles,Bettina Konte,Vaidutis Kučinskas,Zita Ausrele Kucinskiene,Hana Kuzelova-Ptackova,Anna K. Kähler,Claudine Laurent,Jimmy Lee Chee Keong,S. Hong Lee,Sophie E. Legge,Bernard Lerer,Miaoxin Li,Tao Li,Kung-Yee Liang,Jeffrey A. Lieberman,Svetlana A. Limborska,Carmel M. Loughland,Jan Lubinski,Jouko Lönnqvist,Milan Macek,Patrik K. E. Magnusson,Brion S. Maher,Wolfgang Maier,J. Mallet,Sara Marsal,Manuel Mattheisen,Manuel Mattheisen,Manuel Mattheisen,Morten Mattingsdal,Robert W. McCarley,Colm McDonald,Andrew M. McIntosh,Sandra Meier,Carin J. Meijer,Béla Melegh,Ingrid Melle,Raquelle I. Mesholam-Gately,Andres Metspalu,Patricia T. Michie,Lili Milani,Vihra Milanova,Younes Mokrab,Derek W. Morris,Derek W. Morris,Ole Mors,Ole Mors,Kieran C. Murphy,Robin M. Murray,Inez Myin-Germeys,Bertram Mueller-Myhsok,Mari Nelis,Igor Nenadic,Deborah A. Nertney,Gerald Nestadt,Kristin K. Nicodemus,Liene Nikitina-Zake,Laura Nisenbaum,Annelie Nordin,Eadbhard O'Callaghan,Colm O'Dushlaine,F. Anthony O'Neill,Sang-Yun Oh,Ann Olincy,Line Olsen,Jim van Os,Jim van Os,Christos Pantelis,George N. Papadimitriou,Sergi Papiol,Elena Parkhomenko,Michele T. Pato,Tiina Paunio,Tiina Paunio,Milica Pejovic-Milovancevic,Diana O. Perkins,Olli Pietiläinen,Olli Pietiläinen,Jonathan Pimm,Andrew Pocklington,John Powell,Alkes L. Price,Alkes L. Price,Ann E. Pulver,Shaun Purcell,Digby Quested,Henrik B. Rasmussen,Abraham Reichenberg,Mark Reimers,Alexander Richards,Joshua L. Roffman,Panos Roussos,Douglas M. Ruderfer,Douglas M. Ruderfer,Veikko Salomaa,Alan R. Sanders,Ulrich Schall,Christian R. Schubert,Thomas G. Schulze,Thomas G. Schulze,Sibylle G. Schwab,Edward M. Scolnick,Rodney J. Scott,Larry J. Seidman,Jianxin Shi,Engilbert Sigurdsson,Teimuraz Silagadze,Jeremy M. 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Gejman,Michael Gill,Hugh Gurling,Christina M. Hultman,Nakao Iwata,Assen Jablensky,Erik G. Jönsson,Erik G. Jönsson,Kenneth S. Kendler,George Kirov,Jo Knight,Todd Lencz,Todd Lencz,Douglas F. Levinson,Qingqin S. Li,Jianjun Liu,Jianjun Liu,Anil K. Malhotra,Anil K. Malhotra,Steven A. McCarroll,Steven A. McCarroll,Andrew McQuillin,Jennifer L. Moran,Preben Bo Mortensen,Preben Bo Mortensen,Bryan J. Mowry,Markus M. Noethen,Roel A. Ophoff,Roel A. Ophoff,Michael John Owen,Aarno Palotie,Aarno Palotie,Aarno Palotie,Carlos N. Pato,Tracey L. Petryshen,Tracey L. Petryshen,Danielle Posthuma,Danielle Posthuma,Marcella Rietschel,Brien P. Riley,Dan Rujescu,Dan Rujescu,Pak C. Sham,Pamela Sklar,David St Clair,Daniel R. Weinberger,Jens R. Wendland,Thomas Werge,Thomas Werge,Mark J. Daly,Mark J. Daly,Patrick F. Sullivan,Patrick F. Sullivan,Michael Conlon O'Donovan +354 more
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Journal ArticleDOI
Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.
Harvey Whiteford,Harvey Whiteford,Louisa Degenhardt,Louisa Degenhardt,Juergen Rehm,Juergen Rehm,Amanda J Baxter,Amanda J Baxter,Alize J. Ferrari,Alize J. Ferrari,Holly E. Erskine,Holly E. Erskine,Fiona J Charlson,Fiona J Charlson,Rosana E. Norman,Rosana E. Norman,Abraham D. Flaxman,Nicole E. Johns,Roy Burstein,Christopher J L Murray,Theo Vos +20 more
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) as discussed by the authors was used to estimate the burden of disease attributable to mental and substance use disorders in terms of disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs).
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