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Thordur Sigmundsson

Bio: Thordur Sigmundsson is an academic researcher from University of Iceland. The author has contributed to research in topics: Psychosis & Schizophrenia (object-oriented programming). The author has an hindex of 29, co-authored 56 publications receiving 10561 citations. Previous affiliations of Thordur Sigmundsson include King's College London & University College London.


Papers
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Journal ArticleDOI
Hreinn Stefansson1, Dan Rujescu2, Sven Cichon3, Olli Pietiläinen, Andres Ingason1, Stacy Steinberg1, Ragnheidur Fossdal1, Engilbert Sigurdsson, Thordur Sigmundsson, Jacobine E. Buizer-Voskamp4, Thomas Hansen5, Thomas Hansen6, Klaus D. Jakobsen5, Klaus D. Jakobsen6, Pierandrea Muglia7, Clyde Francks7, Paul M. Matthews8, Arnaldur Gylfason1, Bjarni V. Halldorsson1, Daniel F. Gudbjartsson1, Thorgeir E. Thorgeirsson1, Asgeir Sigurdsson1, Adalbjorg Jonasdottir1, Aslaug Jonasdottir1, Asgeir Björnsson1, Sigurborg Mattiasdottir1, Thorarinn Blondal1, Magnús Haraldsson, Brynja B. Magnusdottir, Ina Giegling2, Hans-Jürgen Möller2, Annette M. Hartmann2, Kevin V. Shianna9, Dongliang Ge9, Anna C. Need9, Caroline Crombie10, Gillian Fraser10, Nicholas Walker, Jouko Lönnqvist, Jaana Suvisaari, Annamarie Tuulio-Henriksson, Tiina Paunio, T. Toulopoulou11, Elvira Bramon11, Marta Di Forti11, Robin M. Murray11, Mirella Ruggeri12, Evangelos Vassos11, Sarah Tosato12, Muriel Walshe11, Tao Li11, Tao Li13, Catalina Vasilescu3, Thomas W. Mühleisen3, August G. Wang6, Henrik Ullum6, Srdjan Djurovic14, Ingrid Melle, Jes Olesen15, Lambertus A. Kiemeney16, Barbara Franke16, Chiara Sabatti17, Nelson B. Freimer17, Jeffrey R. Gulcher1, Unnur Thorsteinsdottir1, Augustine Kong1, Ole A. Andreassen14, Roel A. Ophoff4, Roel A. Ophoff17, Alexander Georgi18, Marcella Rietschel18, Thomas Werge6, Hannes Petursson, David Goldstein9, Markus M. Nöthen3, Leena Peltonen19, Leena Peltonen20, David A. Collier11, David A. Collier13, David St Clair10, Kari Stefansson1, Kari Stefansson21 
11 Sep 2008-Nature
TL;DR: In a genome-wide search for CNVs associating with schizophrenia, a population-based sample was used to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring and three deletions significantly associate with schizophrenia and related psychoses in the combined sample.
Abstract: Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

1,767 citations

Journal ArticleDOI
TL;DR: 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.

1,650 citations

Journal ArticleDOI
Hreinn Stefansson1, Hreinn Stefansson2, Roel A. Ophoff2, Roel A. Ophoff3, Roel A. Ophoff4, Stacy Steinberg1, Stacy Steinberg2, Ole A. Andreassen5, Sven Cichon6, Dan Rujescu7, Thomas Werge8, Olli Pietilainen9, Ole Mors10, Preben Bo Mortensen11, Engilbert Sigurdsson12, Omar Gustafsson1, Mette Nyegaard11, Annamari Tuulio-Henriksson13, Andres Ingason1, Thomas Hansen8, Jaana Suvisaari13, Jouko Lönnqvist13, Tiina Paunio, Anders D. Børglum11, Anders D. Børglum10, Annette M. Hartmann7, Anders Fink-Jensen8, Merete Nordentoft14, David M. Hougaard, Bent Nørgaard-Pedersen, Yvonne Böttcher1, Jes Olesen15, René Breuer16, Hans-Jürgen Möller7, Ina Giegling7, Henrik B. Rasmussen8, Sally Timm8, Manuel Mattheisen6, István Bitter17, János Réthelyi17, Brynja B. Magnusdottir12, Thordur Sigmundsson12, Pall I. Olason1, Gisli Masson1, Jeffrey R. Gulcher1, Magnús Haraldsson12, Ragnheidur Fossdal1, Thorgeir E. Thorgeirsson1, Unnur Thorsteinsdottir1, Unnur Thorsteinsdottir12, Mirella Ruggeri18, Sarah Tosato18, Barbara Franke19, Eric Strengman4, Lambertus A. Kiemeney19, Ingrid Melle5, Srdjan Djurovic5, Lilia I. Abramova20, Kaleda Vg20, Julio Sanjuán21, Rosa de Frutos21, Elvira Bramon22, Evangelos Vassos22, Gillian Fraser23, Ulrich Ettinger22, Marco Picchioni22, Nicholas Walker, T. Toulopoulou22, Anna C. Need24, Dongliang Ge24, Joeng Lim Yoon3, Kevin V. Shianna24, Nelson B. Freimer3, Rita M. Cantor3, Robin M. Murray22, Augustine Kong1, Vera Golimbet20, Angel Carracedo25, Celso Arango26, Javier Costas, Erik G. Jönsson27, Lars Terenius27, Ingrid Agartz27, Hannes Petursson12, Markus M. Nöthen6, Marcella Rietschel16, Paul M. Matthews28, Pierandrea Muglia29, Leena Peltonen9, David St Clair23, David Goldstein24, Kari Stefansson12, Kari Stefansson1, David A. Collier30, David A. Collier22 
06 Aug 2009-Nature
TL;DR: Findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
Abstract: Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

1,625 citations

Journal ArticleDOI
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.
Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

1,176 citations

Journal ArticleDOI
TL;DR: The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease and is associated with susceptibility to periodic limb movements in sleep.
Abstract: Background The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. Methods To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. Results In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2×10–9). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4×10–4) and a U.S. sample...

560 citations


Cited by
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08 Oct 2009-Nature
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

7,797 citations

Journal ArticleDOI
31 Jan 2002-Neuron
TL;DR: In this paper, a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set is presented.

7,120 citations

Journal ArticleDOI
Stephan Ripke1, Stephan Ripke2, Benjamin M. Neale2, Benjamin M. Neale1  +351 moreInstitutions (102)
24 Jul 2014-Nature
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.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but 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. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

6,809 citations

Journal ArticleDOI
John W. Belmont1, Paul Hardenbol, Thomas D. Willis, Fuli Yu1, Huanming Yang2, Lan Yang Ch'Ang, Wei Huang3, Bin Liu2, Yan Shen3, Paul K.H. Tam4, Lap-Chee Tsui4, Mary M.Y. Waye5, Jeffrey Tze Fei Wong6, Changqing Zeng2, Qingrun Zhang2, Mark S. Chee7, Luana Galver7, Semyon Kruglyak7, Sarah S. Murray7, Arnold Oliphant7, Alexandre Montpetit8, Fanny Chagnon8, Vincent Ferretti8, Martin Leboeuf8, Michael S. Phillips8, Andrei Verner8, Shenghui Duan9, Denise L. Lind10, Raymond D. Miller9, John P. Rice9, Nancy L. Saccone9, Patricia Taillon-Miller9, Ming Xiao10, Akihiro Sekine, Koki Sorimachi, Yoichi Tanaka, Tatsuhiko Tsunoda, Eiji Yoshino, David R. Bentley11, Sarah E. Hunt11, Don Powell11, Houcan Zhang12, Ichiro Matsuda13, Yoshimitsu Fukushima14, Darryl Macer15, Eiko Suda15, Charles N. Rotimi16, Clement Adebamowo17, Toyin Aniagwu17, Patricia A. Marshall18, Olayemi Matthew17, Chibuzor Nkwodimmah17, Charmaine D.M. Royal16, Mark Leppert19, Missy Dixon19, Fiona Cunningham20, Ardavan Kanani20, Gudmundur A. Thorisson20, Peter E. Chen21, David J. Cutler21, Carl S. Kashuk21, Peter Donnelly22, Jonathan Marchini22, Gilean McVean22, Simon Myers22, Lon R. Cardon22, Andrew P. Morris22, Bruce S. Weir23, James C. Mullikin24, Michael Feolo24, Mark J. Daly25, Renzong Qiu26, Alastair Kent, Georgia M. Dunston16, Kazuto Kato27, Norio Niikawa28, Jessica Watkin29, Richard A. Gibbs1, Erica Sodergren1, George M. Weinstock1, Richard K. Wilson9, Lucinda Fulton9, Jane Rogers11, Bruce W. Birren25, Hua Han2, Hongguang Wang, Martin Godbout30, John C. Wallenburg8, Paul L'Archevêque, Guy Bellemare, Kazuo Todani, Takashi Fujita, Satoshi Tanaka, Arthur L. Holden, Francis S. Collins24, Lisa D. Brooks24, Jean E. McEwen24, Mark S. Guyer24, Elke Jordan31, Jane Peterson24, Jack Spiegel24, Lawrence M. Sung32, Lynn F. Zacharia24, Karen Kennedy29, Michael Dunn29, Richard Seabrook29, Mark Shillito, Barbara Skene29, John Stewart29, David Valle21, Ellen Wright Clayton33, Lynn B. Jorde19, Aravinda Chakravarti21, Mildred K. Cho34, Troy Duster35, Troy Duster36, Morris W. Foster37, Maria Jasperse38, Bartha Maria Knoppers39, Pui-Yan Kwok10, Julio Licinio40, Jeffrey C. Long41, Pilar N. Ossorio42, Vivian Ota Wang33, Charles N. Rotimi16, Patricia Spallone29, Patricia Spallone43, Sharon F. Terry44, Eric S. Lander25, Eric H. Lai45, Deborah A. Nickerson46, Gonçalo R. Abecasis41, David Altshuler47, Michael Boehnke41, Panos Deloukas11, Julie A. Douglas41, Stacey Gabriel25, Richard R. Hudson48, Thomas J. Hudson8, Leonid Kruglyak49, Yusuke Nakamura50, Robert L. Nussbaum24, Stephen F. Schaffner25, Stephen T. Sherry24, Lincoln Stein20, Toshihiro Tanaka 
18 Dec 2003-Nature
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.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

5,926 citations