Large recurrent microdeletions associated with schizophrenia by Stefansson Hreinn, Rujescu Dan, Cichon Sven, Pietiläinen Olli P H, Ingason Andres, Steinberg Stacy, Fossdal Ragnheidur, Sigurdsson Engilbert, Sigmundsson Thordur, Buizer-Voskamp Jacobine E, Hansen Thomas, Jakobsen Klaus D, Muglia Pierandrea, Francks Clyde, Matthews Paul M, Gylfason Arnaldur, Halldorsson Bjarni V, Gudbjartsson Daniel, Thorgeirsson Thorgeir E, Sigurdsson Asgeir, Jonasdottir Adalbjorg, Jonasdottir Aslaug, Bjornsson Asgeir, Mattiasdottir Sigurborg, Blondal Thorarinn, Haraldsson Magnus, Magnusdottir Brynja B, Giegling Ina, Möller Hans-Jürgen, Hartmann Annette, Shianna Kevin V, Ge Dongliang, Need Anna C, Crombie Caroline, Fraser Gillian, Walker Nicholas, Lonnqvist Jouko, Suvisaari Jaana, Tuulio-Henriksson Annamarie, Paunio Tiina, Toulopoulou Timi, Bramon Elvira, Di Forti Marta, Murray Robin, Ruggeri Mirella, Vassos Evangelos, Tosato Sarah, Walshe Muriel, Li Tao, Vasilescu Catalina, Mühleisen Thomas W, Wang August G, Ullum Henrik, Djurovic Srdjan, Melle Ingrid, Olesen Jes, Kiemeney Lambertus A, Franke Barbara, GROUP, Sabatti Chiara, Freimer Nelson B, Gulcher Jeffrey R, Thorsteinsdottir Unnur, Kong Augustine, Andreassen Ole A, Ophoff Roel A, Georgi Alexander, Rietschel Marcella, Werge Thomas, Petursson Hannes, Goldstein David B, Nöthen Markus M, Peltonen Leena, Collier David A, St Clair David, Stefansson Kari in Nature (2008). PubMed

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.

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