Author
Sigurborg Mattiasdottir
Bio: Sigurborg Mattiasdottir is an academic researcher from deCODE genetics. The author has contributed to research in topics: Population & Schizophrenia. The author has an hindex of 1, co-authored 1 publications receiving 1701 citations.
Topics: Population, Schizophrenia
Papers
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deCODE genetics1, Ludwig Maximilian University of Munich2, University of Bonn3, Utrecht University4, Copenhagen University Hospital5, University of Copenhagen6, GlaxoSmithKline7, Hammersmith Hospital8, Duke University9, Royal Cornhill Hospital10, King's College London11, University of Verona12, Sichuan University13, University of Oslo14, Glostrup Hospital15, Radboud University Nijmegen Medical Centre16, University of California, Los Angeles17, Heidelberg University18, Broad Institute19, Wellcome Trust Sanger Institute20, University of Iceland21
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
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National Institutes of Health1, University of Chicago2, Duke University3, Harvard University4, University of Oxford5, GlaxoSmithKline6, Johns Hopkins University7, Yale University8, deCODE genetics9, Howard Hughes Medical Institute10, Princeton University11, Washington University in St. Louis12, University of California, Berkeley13, Stanford University14, University of Michigan15, Cornell University16, University of Washington17, University of Queensland18, Vanderbilt University19, North Carolina State University20, QIMR Berghofer Medical Research Institute21
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
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TL;DR: The dopamine hypothesis of schizophrenia-version III is synthesized into a comprehensive framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function.
Abstract: The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.
2,311 citations
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Boston Children's Hospital1, University of Washington2, Emory University3, GeneDx4, National Institutes of Health5, University of Utah6, Wellcome Trust Sanger Institute7, Salisbury University8, University of California, San Francisco9, Uppsala University10, University of British Columbia11, Johns Hopkins University School of Medicine12, Drexel University13, University of Groningen14, University of Pennsylvania15, University of California, Santa Cruz16, Brigham and Women's Hospital17, The Centre for Applied Genomics18, Research Triangle Park19, Mayo Clinic20, Katholieke Universiteit Leuven21, University of Chicago22, American College of Medical Genetics23
TL;DR: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA).
Abstract: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%–20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (~3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.
2,294 citations
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01 Aug 2009
TL;DR: Mental, emotional, and behavioral (MEB) disorders—which include depression, conduct disorder, and substance abuse—affect large numbers of young people.
Abstract: This report builds on a highly valued predecessor, the 1994 Institute of Medicine (IOM) report entitled Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research. That report provided the basis for understanding prevention science, elucidating its then-existing research base, and contemplating where it should go in the future. This report documents that an increasing number of mental, emotional, and behavioral problems in young people are in fact preventable. The proverbial ounce of prevention will indeed be worth a pound of cure: effectively applying the evidence-based prevention interventions at hand could potentially save billions of dollars in associated costs by avoiding or tempering these disorders in many individuals. Furthermore, devoting significantly greater resources to research on even more effective prevention and promotion efforts, and then reliably implementing the findings of such research, could substantially diminish the human and economic toll.
1,744 citations
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TL;DR: When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases but they were nowhere to be seen.
Abstract: When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases. But they were nowhere to be seen. Brendan Maher shines a light on six places where the missing loot could be stashed away.
1,694 citations