Neuregulin 1 and Susceptibility to Schizophrenia
Hreinn Stefansson,Engilbert Sigurdsson,Valgerdur Steinthorsdottir,Soley Bjornsdottir,Thordur Sigmundsson,Shyamali Ghosh,J Brynjolfsson,Steinunn Gunnarsdottir,Omar Ivarsson,Thomas T. Chou,Omar Hjaltason,Birgitta Birgisdottir,Helgi Jonsson,Vala G. Gudnadottir,Elsa Gudmundsdottir,Asgeir Björnsson,Brynjolfur Ingvarsson,Andres Ingason,Sigmundur Sigfusson,Hronn Hardardottir,Richard P. Harvey,Richard P. Harvey,Donna Lai,Mingdong Zhou,Daniela Brunner,Vincent Mutel,Acuna Gonzalo,Greg Lemke,Jesus Sainz,Gardar Johannesson,Thorkell Andresson,Daniel F. Gudbjartsson,Andrei Manolescu,Michael L. Frigge,Mark E. Gurney,Augustine Kong,Jeffrey R. Gulcher,Hannes Petursson,Kari Stefansson +38 more
TLDR
The results of a genomewide scan of schizophrenia families in Iceland show that schizophrenia maps to chromosome 8p, and extensive fine-mapping of the 8p locus and haplotype-association analysis identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia.Abstract:
The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.read more
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The International HapMap Project
John W. Belmont,Paul Hardenbol,Thomas D. Willis,Fuli Yu,Huanming Yang,Lan Yang Ch'Ang,Wei Huang,Bin Liu,Yan Shen,Paul K.H. Tam,Lap-Chee Tsui,Mary M.Y. Waye,Jeffrey Tze Fei Wong,Changqing Zeng,Qingrun Zhang,Mark S. Chee,Luana Galver,Semyon Kruglyak,Sarah S. Murray,Arnold Oliphant,Alexandre Montpetit,Fanny Chagnon,Vincent Ferretti,Martin Leboeuf,Michael S. Phillips,Andrei Verner,Shenghui Duan,Denise L. Lind,Raymond D. Miller,John P. Rice,Nancy L. Saccone,Patricia Taillon-Miller,Ming Xiao,Akihiro Sekine,Koki Sorimachi,Yoichi Tanaka,Tatsuhiko Tsunoda,Eiji Yoshino,David R. Bentley,Sarah E. Hunt,Don Powell,Houcan Zhang,Ichiro Matsuda,Yoshimitsu Fukushima,Darryl Macer,Eiko Suda,Charles N. Rotimi,Clement Adebamowo,Toyin Aniagwu,Patricia A. Marshall,Olayemi Matthew,Chibuzor Nkwodimmah,Charmaine D.M. Royal,Mark Leppert,Missy Dixon,Fiona Cunningham,Ardavan Kanani,Gudmundur A. Thorisson,Peter E. Chen,David J. Cutler,Carl S. Kashuk,Peter Donnelly,Jonathan Marchini,Gilean McVean,Simon Myers,Lon R. Cardon,Andrew P. Morris,Bruce S. Weir,James C. Mullikin,Michael Feolo,Mark J. Daly,Renzong Qiu,Alastair Kent,Georgia M. Dunston,Kazuto Kato,Norio Niikawa,Jessica Watkin,Richard A. Gibbs,Erica Sodergren,George M. Weinstock,Richard K. Wilson,Lucinda Fulton,Jane Rogers,Bruce W. Birren,Hua Han,Hongguang Wang,Martin Godbout,John C. Wallenburg,Paul L'Archevêque,Guy Bellemare,Kazuo Todani,Takashi Fujita,Satoshi Tanaka,Arthur L. Holden,Francis S. Collins,Lisa D. Brooks,Jean E. McEwen,Mark S. Guyer,Elke Jordan,Jane Peterson,Jack Spiegel,Lawrence M. Sung,Lynn F. Zacharia,Karen Kennedy,Michael Dunn,Richard Seabrook,Mark Shillito,Barbara Skene,John Stewart,David Valle,Ellen Wright Clayton,Lynn B. Jorde,Aravinda Chakravarti,Mildred K. Cho,Troy Duster,Troy Duster,Morris W. Foster,Maria Jasperse,Bartha Maria Knoppers,Pui-Yan Kwok,Julio Licinio,Jeffrey C. Long,Pilar N. Ossorio,Vivian Ota Wang,Charles N. Rotimi,Patricia Spallone,Patricia Spallone,Sharon F. Terry,Eric S. Lander,Eric H. Lai,Deborah A. Nickerson,Gonçalo R. Abecasis,David Altshuler,Michael Boehnke,Panos Deloukas,Julie A. Douglas,Stacey Gabriel,Richard R. Hudson,Thomas J. Hudson,Leonid Kruglyak,Yusuke Nakamura,Robert L. Nussbaum,Stephen F. Schaffner,Stephen T. Sherry,Lincoln Stein,Toshihiro Tanaka +145 more
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
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Genome-wide association studies for common diseases and complex traits
TL;DR: Genome-wide association studies will soon become possible, and could open new frontiers in the understanding and treatment of disease, however, the execution and analysis of such studies will require great care.
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Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.
TL;DR: Despite evidence of heterogeneity across studies, meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences.
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Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
TL;DR: This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry.
Journal ArticleDOI
Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia
Cathryn M. Lewis,Douglas F. Levinson,Lesley H. Wise,Lynn E. DeLisi,Richard E. Straub,Iiris Hovatta,Nigel Williams,Sibylle G. Schwab,Ann E. Pulver,Stephen V. Faraone,Linda M. Brzustowicz,Linda M. Brzustowicz,Charles A. Kaufmann,David L. Garver,Hugh Gurling,Eva Lindholm,Hilary Coon,Hans W. Moises,William Byerley,Sarah H. Shaw,Andrea Mesén,Robin Sherrington,F. Anthony O'Neill,Dermot Walsh,Kenneth S. Kendler,Jesper Ekelund,Tiina Paunio,Jouko Lönnqvist,Leena Peltonen,Leena Peltonen,Michael Conlon O'Donovan,Michael John Owen,Dieter B. Wildenauer,Wolfgang Maier,Gerald Nestadt,Jean-Louis Blouin,Stylianos E. Antonarakis,Bryan J. Mowry,Jeremy M. Silverman,Raymond R. Crowe,C. Robert Cloninger,Ming T. Tsuang,Dolores Malaspina,Jill M. Harkavy-Friedman,Dragan M. Svrakic,Anne S. Bassett,Jennifer A. Holcomb,Gursharan Kalsi,Andrew McQuillin,Jon Brynjolfson,Thordur Sigmundsson,Hannes Petursson,Elena Jazin,Tómas Zoega,Tómas Helgason +54 more
TL;DR: The GSMA produced significant genomewide evidence for linkage on chromosome 2q and suggests that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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