The DISC locus and schizophrenia

Evidence from an association study in a central European sample and from a meta-analysis across different European populations

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

Research output: Contribution to journalArticle

Abstract

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 × 10-5) and contributed most strongly to early-onset cases (P = 9 × 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 (US)
Pages (from-to)2719-2727
Number of pages9
JournalHuman Molecular Genetics
Volume18
Issue number14
DOIs
StatePublished - 2009
Externally publishedYes

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Meta-Analysis
Schizophrenia
Population
Single Nucleotide Polymorphism
Odds Ratio
Introns
Chromosome Mapping
Genotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

The DISC locus and schizophrenia : Evidence from an association study in a central European sample and from a meta-analysis across different European populations. / Schumacher, Johannes; Laje, Gonzalo; Jamra, Rami Abou; Becker, Tim; Mühleisen, Thomas W.; Vasilescu, Catalina; Mattheisen, Manuel; Herms, Stefan; Hoffmann, Per; Hillmer, Axel M.; Georgi, Alexander; Herold, Christine; Schulze, Thomas G.; Propping, Peter; Rietschel, Marcella; McMahon, Francis J.; Nöthen, Markus M.; Cichon, Sven.

In: Human Molecular Genetics, Vol. 18, No. 14, 2009, p. 2719-2727.

Research output: Contribution to journalArticle

Schumacher, J, Laje, G, Jamra, RA, Becker, T, Mühleisen, TW, Vasilescu, C, Mattheisen, M, Herms, S, Hoffmann, P, Hillmer, AM, Georgi, A, Herold, C, Schulze, TG, Propping, P, Rietschel, M, McMahon, FJ, Nöthen, MM & Cichon, S 2009, 'The DISC locus and schizophrenia: Evidence from an association study in a central European sample and from a meta-analysis across different European populations', Human Molecular Genetics, vol. 18, no. 14, pp. 2719-2727. https://doi.org/10.1093/hmg/ddp204
Schumacher, Johannes ; Laje, Gonzalo ; Jamra, Rami Abou ; Becker, Tim ; Mühleisen, Thomas W. ; Vasilescu, Catalina ; Mattheisen, Manuel ; Herms, Stefan ; Hoffmann, Per ; Hillmer, Axel M. ; Georgi, Alexander ; Herold, Christine ; Schulze, Thomas G. ; Propping, Peter ; Rietschel, Marcella ; McMahon, Francis J. ; Nöthen, Markus M. ; Cichon, Sven. / The DISC locus and schizophrenia : Evidence from an association study in a central European sample and from a meta-analysis across different European populations. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 14. pp. 2719-2727.
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AU - Laje, Gonzalo

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AU - Becker, Tim

AU - Mühleisen, Thomas W.

AU - Vasilescu, Catalina

AU - Mattheisen, Manuel

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Hillmer, Axel M.

AU - Georgi, Alexander

AU - Herold, Christine

AU - Schulze, Thomas G.

AU - Propping, Peter

AU - Rietschel, Marcella

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N2 - 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 × 10-5) and contributed most strongly to early-onset cases (P = 9 × 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.

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