1. ¹Medical Genetics Section, University of Edinburgh, Edinburgh, Scotland
2. ²Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
3. ³Molecular Psychiatry Laboratory, Department of Mental Health Science, Windeyer Institute of Medical Sciences, University College London, London, England
4. ⁴Finnish Genome Center, University of Helsinki, Helsinki, Finland
5. ⁵Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland
6. ⁶Queen Mary College, University of London, London, England
7. ⁷City Mental Health Trust, Royal London Hospital, London, England
8. ⁸Department of Psychology, University of Edinburgh, Edinburgh, Scotland
9. ⁹Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
10. ¹⁰Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland
11. ¹¹Department of Psychiatry, Jorvi Hospital, Helsinki University Central Hospital, Espoo, Finland
12. ¹²Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland
13. ¹³Department of Medical Genetics, University of Helsinki, Helsinki, Finland
14. ¹⁴The Broad Institute, Massachusetts Institute of Technology, Boston, MA, USA

Correspondence: Dr W Hennah, Medical Genetics Section, University of Edinburgh, Edinburgh EH4 2XU, UK. E-mail: william.hennah@ed.ac.uk

Received 14 September 2007; Revised 17 December 2007; Accepted 20 December 2007; Published online 4 March 2008.

Abstract

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.7395% confidence interval (CI) 1.42–5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.6495% CI 1.23–2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.2795% CI 1.07–1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.