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Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms

Molecular Psychiatry volume 14, pages 786–795 (2009)Cite this article

Abstract

A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker–marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region.

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Acknowledgements

We thank the many family members who participated in the studies that recruited these samples. This work was supported by National Institute of Mental Health grants 7R01MH062276 (to DFL, CL, MO and DW), 5R01MH068922 (to PG), 5R01MH068921 (to AEP) and 5R01MH068881 (to BR). For the NIMH sample, data and biomaterials were collected in three projects that participated in the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative. From 1991 to 97, the principal investigators and co-investigators were: Harvard University, Boston, MA, U01 MH46318, Ming T Tsuang, Stephen Faraone and John Pepple; Washington University, St Louis, MO, U01 MH46276, C Robert Cloninger, Theodore Reich and Dragan Svrakic; Columbia University, New York, NY U01 MH46289, Charles Kaufmann, Dolores Malaspina and Jill Harkavy Friedman. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number N01-HG-65403. The NIMH Cell Repository at Rutgers University (Dr Douglas Fugman and Dr Jay Tischfield) and the NIMH Center for Collaborative Genetic Studies on Mental Disorders (Dr John Rice) made important contributions to this project.

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Authors and Affiliations

  1. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK

    P A Holmans, M J Owen, N M Williams, M C O'Donovan & N Norton

  2. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    B Riley, K S Kendler, B Wormley & R Ribble

  3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A E Pulver, G Nestadt & V K Lasseter

  4. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia

    D B Wildenauer & S G Schwab

  5. Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Mt Claremont, WA, Australia

    D B Wildenauer

  6. Center for Psychiatric Genetics, Evanston Northwestern Healthcare Research Institute, Northwestern University, Evanston, IL, USA

    P V Gejman, A R Sanders & J Duan

  7. Queensland Centre for Mental Health Research, University of Queensland, Brisbane, QLD, Australia

    B J Mowry & D Nertney

  8. Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France

    C Laurent & M Jay

  9. School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia

    S G Schwab

  10. Centre for Medical Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA, Australia

    S G Schwab

  11. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Centre National de la Recherche Scientifique, Hôpital de la Pitié Salpêtrière, Paris, France

    J Mallet

  12. State Mental Hospital, Haar, Germany

    M Albus

  13. Department of Psychiatry, Stanford University, Stanford, CA, USA

    M Alexander & D F Levinson

  14. INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France

    S Godard

  15. Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    K Y Liang

  16. Department of Psychiatry, University of Bonn, Bonn, Germany

    W Maier

  17. Department of Psychiatry, University of Athens Medical School, Athens, Greece

    G Papadimitriou & D Dikeos

  18. The Health Research Board, Dublin, Ireland

    D Walsh

  19. Department of Psychiatry, Queens University, Belfast, Ireland

    A O'Neill

  20. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    F B Lerer

  21. Department of Psychiatry, The University of Iowa College of Medicine, Iowa City, IW, USA

    R R Crowe

  22. Department of Psychiatry, Mt Sinai School of Medicine, New York, NY, USA

    J M Silverman

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Correspondence to D F Levinson.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Holmans, P., Riley, B., Pulver, A. et al. Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms. Mol Psychiatry 14, 786–795 (2009). https://doi.org/10.1038/mp.2009.11

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