Manuel Mattheisen

The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Johannes Schumacher
  • ,
  • Gonzalo Laje
  • ,
  • Rami Abou Jamra
  • ,
  • Tim Becker
  • ,
  • Thomas W Mühleisen
  • ,
  • Catalina Vasilescu
  • ,
  • Manuel Mattheisen
  • Stefan Herms
  • ,
  • Per Hoffmann
  • ,
  • Axel M Hillmer
  • ,
  • Alexander Georgi
  • ,
  • Christine Herold
  • ,
  • Thomas G Schulze
  • ,
  • Peter Propping
  • ,
  • Marcella Rietschel
  • ,
  • Francis J McMahon
  • ,
  • Markus M Nöthen
  • ,
  • Sven Cichon
Association studies, as well as the initial translocation family study, identified the gene Disrupted-In-Schizophrenia-1 (DISC1) as a risk factor for schizophrenia. DISC1 encodes a multifunctional scaffold protein involved in neurodevelopmental processes implicated in the etiology of schizophrenia. The present study explores the contribution of the DISC locus to schizophrenia using three different approaches: (i) systematic association mapping aimed at detecting DISC risk variants in a schizophrenia sample from a central European population (556 SNPs, n = 1621 individuals). In this homogenous sample, a circumscribed DISC1 interval in intron 9 was significantly associated with schizophrenia in females (P = 4 x 10(-5)) and contributed most strongly to early-onset cases (P = 9 x 10(-5)). The odds ratios (ORs) were in the range of 1.46-1.88. (ii) The same sample was used to test for the locus-specific SNP-SNP interaction most recently associated with schizophrenia. Our results confirm the SNP interplay effect between rs1538979 and rs821633 that significantly conferred disease risk in male patients with schizophrenia (P = 0.016, OR 1.57). (iii) In order to detect additional schizophrenia variants, a meta-analysis was performed using nine schizophrenia samples from different European populations (50 SNPs, n = 10 064 individuals maximum, n = 3694 minimum). We found evidence for a common schizophrenia risk interval within DISC1 intron 4-6 (P = 0.002, OR 1.27). The findings point to a complex association between schizophrenia and DISC, including the presence of different risk loci and SNP interplay effects. Furthermore, our phenotype-genotype results--including the consideration of sex-specific effects--highlight the value of homogenous samples in mapping risk genes for schizophrenia in general, and at the DISC locus in particular.
Original languageEnglish
JournalHuman Molecular Genetics
Volume18
Issue14
Pages (from-to)2719-27
Number of pages9
ISSN0964-6906
DOIs
Publication statusPublished - 15 Jul 2009

    Research areas

  • Case-Control Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genotype, Humans, Introns, Male, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Schizophrenia, Sex Factors

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