Schizophrenia: a common disease caused by multiple rare alleles
Reads0
Chats0
TLDR
It is suggested that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families.Abstract:
Schizophrenia is widely held to stem from the combined effects of multiple common polymorphisms, each with a small impact on disease risk. We suggest an alternative view: that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families. This "common disease--rare alleles" hypothesis is supported by recent findings in human genomics and by allelic and locus heterogeneity for other complex traits. We review the implications of this model for gene discovery research in schizophrenia.read more
Citations
More filters
Journal ArticleDOI
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
Shaun Purcell,Shaun Purcell,Naomi R. Wray,Jennifer Stone,Jennifer Stone,Peter M. Visscher,Michael Conlon O'Donovan,Patrick F. Sullivan,Pamela Sklar,Pamela Sklar,Douglas M. Ruderfer,Andrew McQuillin,Derek W. Morris,Colm O'Dushlaine,Aiden Corvin,Peter Holmans,Stuart MacGregor,Hugh Gurling,Douglas Blackwood,Nicholas John Craddock,Michael Gill,Christina M. Hultman,Christina M. Hultman,George Kirov,Paul Lichtenstein,Walter J. Muir,Michael John Owen,Carlos N. Pato,Edward M. Scolnick,Edward M. Scolnick,David St Clair,Nigel Williams,Lyudmila Georgieva,Ivan Nikolov,Nadine Norton,Hywel Williams,Draga Toncheva,Vihra Milanova,Emma Flordal Thelander,Patrick Sullivan,Elaine Kenny,Emma M. Quinn,Khalid Choudhury,Susmita Datta,Jonathan Pimm,Srinivasa Thirumalai,Vinay Puri,Robert Krasucki,Jacob Lawrence,Digby Quested,Nicholas Bass,Caroline Crombie,Gillian Fraser,Soh Leh Kuan,Nicholas Walker,Kevin A. McGhee,Ben S. Pickard,P. Malloy,Alan W Maclean,Margaret Van Beck,Michele T. Pato,Helena Medeiros,Frank A. Middleton,Célia Barreto Carvalho,Christopher P. Morley,Ayman H. Fanous,David V. Conti,James A. Knowles,Carlos Ferreira,António Macedo,M. Helena Azevedo,Andrew Kirby,Andrew Kirby,Manuel A. R. Ferreira,Manuel A. R. Ferreira,Mark J. Daly,Mark J. Daly,Kimberly Chambert,Finny G Kuruvilla,Stacey Gabriel,Kristin G. Ardlie,Jennifer L. Moran +81 more
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Journal ArticleDOI
Five years of GWAS discovery
Peter M. Visscher,Peter M. Visscher,Matthew A. Brown,Mark I. McCarthy,Mark I. McCarthy,Jian Yang +5 more
TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Journal ArticleDOI
Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Tom Walsh,Jon McClellan,Shane McCarthy,Anjené M. Addington,Sarah B. Pierce,Greg M. Cooper,Alexander Nord,Mary Kusenda,Mary Kusenda,Dheeraj Malhotra,Abhishek Bhandari,Sunday M. Stray,Caitlin Rippey,Patricia Roccanova,Vlad Makarov,B. Lakshmi,Robert L. Findling,Linmarie Sikich,Linmarie Sikich,Thomas Stromberg,Barry Merriman,Nitin Gogtay,Philip Butler,Kristen L. Eckstrand,Laila Noory,Peter Gochman,Robert Long,Zugen Chen,Sean Davis,Carl Baker,Evan E. Eichler,Paul S. Meltzer,Stanley F. Nelson,Andrew B. Singleton,Ming K. Lee,Judith L. Rapoport,Mary Claire King,Jonathan Sebat +37 more
TL;DR: The results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia, and disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways.
Journal ArticleDOI
De novo mutations in schizophrenia implicate synaptic networks
Menachem Fromer,Andrew Pocklington,David J. Kavanagh,Hywel Williams,Sarah Dwyer,Padhraig Gormley,Lyudmila Georgieva,Elliott Rees,Priit Palta,Douglas M. Ruderfer,Noa Carrera,Isla Humphreys,Jessica S. Johnson,Panos Roussos,Douglas Barker,Eric Banks,Vihra Milanova,Seth G. N. Grant,Eilis Hannon,Samuel A. Rose,Kimberly Chambert,Milind Mahajan,Edward M. Scolnick,Jennifer L. Moran,George Kirov,Aarno Palotie,Steven A. McCarroll,Peter Holmans,Pamela Sklar,Michael John Owen,Shaun Purcell,Michael Conlon O'Donovan +31 more
TL;DR: Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways, and pathophysiology shared with other neurodevelopmental disorders.
Journal ArticleDOI
Rare and common variants: twenty arguments
TL;DR: 20 arguments for and against each of these models of the genetic basis of complex traits are reviewed and it is concluded that both classes of effect can be readily reconciled.
References
More filters
Journal ArticleDOI
Initial sequencing and analysis of the human genome.
Eric S. Lander,Lauren Linton,Bruce W. Birren,Chad Nusbaum,Michael C. Zody,Jennifer Baldwin,Keri Devon,Ken Dewar,Michael Doyle,William Fitzhugh,Roel Funke,Diane Gage,Katrina Harris,Andrew Heaford,John Howland,Lisa Kann,Jessica A. Lehoczky,Rosie Levine,Paul A. McEwan,Kevin McKernan,James Meldrim,Jill P. Mesirov,Cher Miranda,William Morris,Jerome Naylor,Christina Raymond,Mark Rosetti,Ralph Santos,Andrew Sheridan,Carrie Sougnez,Nicole Stange-Thomann,Nikola Stojanovic,Aravind Subramanian,Dudley Wyman,Jane Rogers,John Sulston,R Ainscough,Stephan Beck,David Bentley,John Burton,C M Clee,Nigel P. Carter,Alan Coulson,Rebecca Deadman,Panos Deloukas,Andrew Dunham,Ian Dunham,Richard Durbin,Lisa French,Darren Grafham,Simon G. Gregory,Tim Hubbard,Sean Humphray,Adrienne Hunt,Matthew Jones,Christine Lloyd,Amanda McMurray,Lucy Matthews,Simon Mercer,Sarah Milne,James C. Mullikin,Andrew J. Mungall,Robert W. Plumb,Mark T. Ross,Ratna Shownkeen,Sarah Sims,Robert H. Waterston,Richard K. Wilson,LaDeana W. Hillier,John Douglas Mcpherson,Marco A. Marra,Elaine R. Mardis,Lucinda Fulton,Asif T. Chinwalla,Kymberlie H. Pepin,Warren Gish,Stephanie L. Chissoe,Michael C. Wendl,Kim D. Delehaunty,Tracie L. Miner,Andrew Delehaunty,Jason B. Kramer,Lisa Cook,Robert S. Fulton,Douglas L. Johnson,Patrick Minx,Sandra W. Clifton,Trevor Hawkins,Elbert Branscomb,Paul Predki,Paul G. Richardson,Sarah Wenning,Tom Slezak,Norman A. Doggett,Jan Fang Cheng,Anne S. Olsen,Susan Lucas,Christopher J. Elkin,Edward Uberbacher,Marvin Frazier,Richard A. Gibbs,Donna M. Muzny,Steven E. Scherer,John Bouck,Erica Sodergren,Kim C. Worley,Catherine M. Rives,James H. Gorrell,Michael L. Metzker,Susan L. Naylor,Raju Kucherlapati,David L. Nelson,George M. Weinstock,Yoshiyuki Sakaki,Asao Fujiyama,Masahira Hattori,Tetsushi Yada,Atsushi Toyoda,Takehiko Itoh,Chiharu Kawagoe,Hidemi Watanabe,Yasushi Totoki,Todd D. Taylor,Jean Weissenbach,Roland Heilig,William Saurin,François Artiguenave,Philippe Brottier,Thomas Brüls,Eric Pelletier,Catherine Robert,Patrick Wincker,André Rosenthal,Matthias Platzer,Gerald Nyakatura,Stefan Taudien,Andreas Rump,Douglas R. Smith,Lynn Doucette-Stamm,Marc Rubenfield,Keith Weinstock,Mei Lee Hong,Joann Dubois,Huanming Yang,Jun Yu,Jian Wang,Guyang Huang,Jun Gu,Leroy Hood,Lee Rowen,Anup Madan,Shizen Qin,Ronald W. Davis,Nancy A. Federspiel,A. Pia Abola,Michael Proctor,Bruce A. Roe,Feng Chen,Huaqin Pan,Juliane Ramser,Hans Lehrach,Richard Reinhardt,W. Richard McCombie,Melissa De La Bastide,Neilay Dedhia,H. Blöcker,K. Hornischer,Gabriele Nordsiek,Richa Agarwala,L. Aravind,Jeffrey A. Bailey,Alex Bateman,Serafim Batzoglou,Ewan Birney,Peer Bork,Daniel G. Brown,Christopher B. Burge,Lorenzo Cerutti,Hsiu Chuan Chen,Deanna M. Church,Michele Clamp,Richard R. Copley,Tobias Doerks,Sean R. Eddy,Evan E. Eichler,Terrence S. Furey,James E. Galagan,James G. R. Gilbert,Cyrus L. Harmon,Yoshihide Hayashizaki,David Haussler,Henning Hermjakob,Karsten Hokamp,Wonhee Jang,L. Steven Johnson,Thomas A. Jones,Simon Kasif,Arek Kaspryzk,Scot Kennedy,W. James Kent,Paul Kitts,Eugene V. Koonin,Ian F Korf,David Kulp,Doron Lancet,Todd M. Lowe,Aoife McLysaght,Tarjei S. Mikkelsen,John V. Moran,Nicola Mulder,Victor J. Pollara,Chris P. Ponting,Greg Schuler,Jörg Schultz,Guy Slater,Arian F.A. Smit,Elia Stupka,Joseph Szustakowki,Danielle Thierry-Mieg,Jean Thierry-Mieg,Lukas Wagner,John W. Wallis,Raymond Wheeler,Alan Williams,Yuri I. Wolf,Kenneth H. Wolfe,Shiaw Pyng Yang,Ru Fang Yeh,Francis S. Collins,Mark S. Guyer,Jane Peterson,Adam Felsenfeld,Kris A. Wetterstrand,Richard M. Myers,Jeremy Schmutz,Mark Dickson,Jane Grimwood,David R. Cox,Maynard V. Olson,Rajinder Kaul,Christopher K. Raymond,Nobuyoshi Shimizu,Kazuhiko Kawasaki,Shinsei Minoshima,Glen A. Evans,Maria Athanasiou,Roger A. Schultz,Aristides Patrinos,Michael J. Morgan +248 more
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Journal ArticleDOI
Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals
Rudolf Jaenisch,Adrian Bird +1 more
TL;DR: Advances in the understanding of the mechanism and role of DNA methylation in biological processes are reviewed, showing that epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression.
Journal ArticleDOI
Cancer genes and the pathways they control.
TL;DR: The purposes of this review are to highlight examples of progress in many areas of cancer research, indicate where knowledge is scarce and point out fertile grounds for future investigation.
Journal ArticleDOI
Finishing the euchromatic sequence of the human genome
Chris P. Ponting,Daniel Barker +1 more
TL;DR: The current human genome sequence (Build 35) as discussed by the authors contains 2.85 billion nucleotides interrupted by only 341 gaps and is accurate to an error rate of approximately 1 event per 100,000 bases.
Journal ArticleDOI
Epigenetic differences arise during the lifetime of monozygotic twins
Mario F. Fraga,Esteban Ballestar,Maria F. Paz,Santiago Ropero,Fernando Setien,Maria Luisa Ballestar,Damia Heine-Suñer,Juan C. Cigudosa,Miguel Urioste,Javier Benitez,Manuel Boix-Chornet,Abel Sánchez-Aguilera,Charlotte Ling,Emma Carlsson,Pernille Poulsen,Allan Vaag,Zarko Stephan,Tim D. Spector,Yue Zhong Wu,Christoph Plass,Manel Esteller +20 more
TL;DR: Older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait, indicating how an appreciation of epigenetics is missing from the understanding of how different phenotypes can be originated from the same genotype.
Related Papers (5)
Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Tom Walsh,Jon McClellan,Shane McCarthy,Anjené M. Addington,Sarah B. Pierce,Greg M. Cooper,Alexander Nord,Mary Kusenda,Mary Kusenda,Dheeraj Malhotra,Abhishek Bhandari,Sunday M. Stray,Caitlin Rippey,Patricia Roccanova,Vlad Makarov,B. Lakshmi,Robert L. Findling,Linmarie Sikich,Linmarie Sikich,Thomas Stromberg,Barry Merriman,Nitin Gogtay,Philip Butler,Kristen L. Eckstrand,Laila Noory,Peter Gochman,Robert Long,Zugen Chen,Sean Davis,Carl Baker,Evan E. Eichler,Paul S. Meltzer,Stanley F. Nelson,Andrew B. Singleton,Ming K. Lee,Judith L. Rapoport,Mary Claire King,Jonathan Sebat +37 more
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
Shaun Purcell,Shaun Purcell,Naomi R. Wray,Jennifer Stone,Jennifer Stone,Peter M. Visscher,Michael Conlon O'Donovan,Patrick F. Sullivan,Pamela Sklar,Pamela Sklar,Douglas M. Ruderfer,Andrew McQuillin,Derek W. Morris,Colm O'Dushlaine,Aiden Corvin,Peter Holmans,Stuart MacGregor,Hugh Gurling,Douglas Blackwood,Nicholas John Craddock,Michael Gill,Christina M. Hultman,Christina M. Hultman,George Kirov,Paul Lichtenstein,Walter J. Muir,Michael John Owen,Carlos N. Pato,Edward M. Scolnick,Edward M. Scolnick,David St Clair,Nigel Williams,Lyudmila Georgieva,Ivan Nikolov,Nadine Norton,Hywel Williams,Draga Toncheva,Vihra Milanova,Emma Flordal Thelander,Patrick Sullivan,Elaine Kenny,Emma M. Quinn,Khalid Choudhury,Susmita Datta,Jonathan Pimm,Srinivasa Thirumalai,Vinay Puri,Robert Krasucki,Jacob Lawrence,Digby Quested,Nicholas Bass,Caroline Crombie,Gillian Fraser,Soh Leh Kuan,Nicholas Walker,Kevin A. McGhee,Ben S. Pickard,P. Malloy,Alan W Maclean,Margaret Van Beck,Michele T. Pato,Helena Medeiros,Frank A. Middleton,Célia Barreto Carvalho,Christopher P. Morley,Ayman H. Fanous,David V. Conti,James A. Knowles,Carlos Ferreira,António Macedo,M. Helena Azevedo,Andrew Kirby,Andrew Kirby,Manuel A. R. Ferreira,Manuel A. R. Ferreira,Mark J. Daly,Mark J. Daly,Kimberly Chambert,Finny G Kuruvilla,Stacey Gabriel,Kristin G. Ardlie,Jennifer L. Moran +81 more
Large recurrent microdeletions associated with schizophrenia
Hreinn Stefansson,Dan Rujescu,Sven Cichon,Olli Pietiläinen,Andres Ingason,Stacy Steinberg,Ragnheidur Fossdal,Engilbert Sigurdsson,Thordur Sigmundsson,Jacobine E. Buizer-Voskamp,Thomas Hansen,Thomas Hansen,Klaus D. Jakobsen,Klaus D. Jakobsen,Pierandrea Muglia,Clyde Francks,Paul M. Matthews,Arnaldur Gylfason,Bjarni V. Halldorsson,Daniel F. Gudbjartsson,Thorgeir E. Thorgeirsson,Asgeir Sigurdsson,Adalbjorg Jonasdottir,Aslaug Jonasdottir,Asgeir Björnsson,Sigurborg Mattiasdottir,Thorarinn Blondal,Magnús Haraldsson,Brynja B. Magnusdottir,Ina Giegling,Hans-Jürgen Möller,Annette M. Hartmann,Kevin V. Shianna,Dongliang Ge,Anna C. Need,Caroline Crombie,Gillian Fraser,Nicholas Walker,Jouko Lönnqvist,Jaana Suvisaari,Annamarie Tuulio-Henriksson,Tiina Paunio,T. Toulopoulou,Elvira Bramon,Marta Di Forti,Robin M. Murray,Mirella Ruggeri,Evangelos Vassos,Sarah Tosato,Muriel Walshe,Tao Li,Tao Li,Catalina Vasilescu,Thomas W. Mühleisen,August G. Wang,Henrik Ullum,Srdjan Djurovic,Ingrid Melle,Jes Olesen,Lambertus A. Kiemeney,Barbara Franke,Chiara Sabatti,Nelson B. Freimer,Jeffrey R. Gulcher,Unnur Thorsteinsdottir,Augustine Kong,Ole A. Andreassen,Roel A. Ophoff,Roel A. Ophoff,Alexander Georgi,Marcella Rietschel,Thomas Werge,Hannes Petursson,David Goldstein,Markus M. Nöthen,Leena Peltonen,Leena Peltonen,David A. Collier,David A. Collier,David St Clair,Kari Stefansson,Kari Stefansson +81 more
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat,B. Lakshmi,Dheeraj Malhotra,Jennifer Troge,Christa Lese-Martin,Tom Walsh,Boris Yamrom,Seungtai Yoon,Alexander Krasnitz,Jude Kendall,Anthony Leotta,Deepa Pai,Ray Zhang,Yoon-ha Lee,James W. Hicks,Sarah J. Spence,Annette Lee,Kaija Puura,Terho Lehtimäki,David H. Ledbetter,Peter K. Gregersen,Joel D. Bregman,James S. Sutcliffe,Vaidehi Jobanputra,Wendy K. Chung,Dorothy Warburton,Mary Claire King,David Skuse,Daniel H. Geschwind,T. Conrad Gilliam,Kenny Ye,Michael Wigler +31 more