Human Molecular Genetics Advance Access originally published online on May 4, 2009
Human Molecular Genetics 2009 18(14):2719-2727; doi:10.1093/hmg/ddp204
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The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations
1 Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), US Department of Health and Human Services (DHHS), Bethesda, MD, USA 2 Institute of Human Genetics 3 Institute for Medical Biometry, Informatics and Epidemiology 4 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany 5 Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
* To whom correspondence should be addressed at: Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), US Department of Health and Human Services (DHHS), 35 Convent Drive, Building 35, Room A202, Bethesda, MD 20892 3719, USA. Tel: +1 3014514249; Fax: +1 3014027094; Email: schumacherj{at}mail.nih.gov
Received March 24, 2009; Accepted April 28, 2009
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.