Large recurrent microdeletions associated with schizophrenia.


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.

DOI: 10.1038/nature07229

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@article{Stefansson2008LargeRM, title={Large recurrent microdeletions associated with schizophrenia.}, author={Hreinn Stefansson and Dan Rujescu and Sven Cichon and Olli P H Pietil{\"a}inen and Andres Ingason and Stacy Steinberg and Ragnheidur Fossdal and Engilbert Sigurdsson and Thordur Sigmundsson and Jacobine E Buizer-Voskamp and Thomas Hansen and Klaus D Jakobsen and Pierandrea Muglia and Clyde Francks and Paul M Matthews and Arnaldur Gylfason and Bjarni V Halldorsson and Daniel Gudbjartsson and Thorgeir E Thorgeirsson and Asgeir Sigurdsson and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Asgeir Bjornsson and Sigurborg Mattiasdottir and Thorarinn Blondal and Magnus Haraldsson and Brynja B Magnusdottir and Ina Giegling and Hans-J{\"{u}rgen M{\"{o}ller and Annette Hartmann and Kevin V Shianna and Dongliang Ge and Anna C Need and Caroline Crombie and Gillian Fraser and Nicholas Walker and Jouko Lonnqvist and Jaana Suvisaari and Annamarie Tuulio-Henriksson and Tiina Paunio and Timi Toulopoulou and Elvira Bramon and Marta Di Forti and Robin Murray and Mirella Ruggeri and Evangelos Vassos and Sarah Tosato and Muriel Walshe and Tao Li and Catalina Vasilescu and Thomas W M{\"{u}hleisen and August G Wang and Henrik Ullum and Srdjan Djurovic and Ingrid Melle and Jes Olesen and Lambertus A Kiemeney and Barbara Franke and Chiara Sabatti and Nelson B Freimer and Jeffrey R Gulcher and Unnur Thorsteinsdottir and Augustine Kong and Ole A Andreassen and Roel A Ophoff and Alexander Georgi and Marcella Rietschel and Thomas Werge and Hannes Petursson and David B Goldstein and Markus M N{\"{o}then and Leena Peltonen and David A Collier and David St Clair and Kari Stefansson}, journal={Nature}, year={2008}, volume={455 7210}, pages={232-6} }