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Operation of the Schizophrenia Susceptibility Gene, Neuregulin 1, Across Traditional Diagnostic Boundaries to Increase Risk for Bipolar Disorder
Elaine K. Green, PhD;
Rachel Raybould, BSc;
Stuart Macgregor, PhD;
Katherine Gordon-Smith, BSc;
Jess Heron, BA;
Sally Hyde, BSc;
Detelina Grozeva, MSc;
Marian Hamshere, PhD;
Nigel Williams, PhD;
Michael J. Owen, PhD, FRCPsych;
Michael C. O’Donovan, PhD, FRCPsych;
Lisa Jones, PhD;
Ian Jones, PhD, MRCPsych;
George Kirov, MD, MRCPsych;
Nick Craddock, MB, PhD
Arch Gen Psychiatry. 2005;62:642-648.
Context Family and twin data suggest that, in addition to susceptibility genes specific for bipolar disorder or schizophrenia, genes exist that contribute to susceptibility across the traditional kraepelinian divide. Several studies have provided evidence that variation at the neuregulin 1 (NRG1) gene on chromosome 8p12 influences susceptibility to schizophrenia. The most consistent finding has been that one particular haplotype (the "core" haplotype) is overrepresented in cases compared with control subjects.
Objective To investigate the possible role of NRG1 in bipolar disorder.
Design Genetic case-control association analysis.
Setting Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services.
Participants Five hundred twenty-nine patients with DSM-IV bipolar I disorder and 1011 controls from the United Kingdom (100% white).
Methods We genotyped the markers constituting the NRG1 core haplotype in cases and controls and reanalyzed our existing data from 573 DSM-IV schizophrenia cases with this larger set of controls.
Results We found a significant difference in haplotype distribution between bipolar cases and controls globally (P = .003) and specifically for the core haplotype. Frequencies were 10.2% for bipolar cases and 7.8% for controls (effect size, as measured by odds ratio [OR], 1.37; 95% confidence interval [CI], 1.03-1.80; P = .04). The effect size in our bipolar sample was similar to that in our schizophrenia sample (OR, 1.22; 95% CI, 0.92-1.61). In the bipolar cases with predominantly mood-incongruent psychotic features (n = 193), the effect was greater (OR, 1.71; 95% CI, 1.29-2.59; P = .009), as was the case in the subset of schizophrenia cases (n = 27) who had experienced mania (OR, 1.64; 95% CI, 0.54-5.01).
Conclusions Our findings suggest that neuregulin 1 plays a role in influencing susceptibility to bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychosis that has manic and mood-incongruent psychotic features.
Author Affiliations: Department of Psychological Medicine (Drs Green, Hamshere, Williams, Owen, O’Donovan, I. Jones, Kirov, and Craddock and Mss Raybould and Grozeva) and Biostatics and Bioinformatics Unit (Drs Macgregor and Hamshere), University of Wales College of Medicine, Cardiff; and Division of Neuroscience, Department of Psychiatry, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, England (Dr L. Jones and Mss Gordon-Smith, Heron, and Hyde).
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