Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder.
BACKGROUND
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.


METHODS
Genetic case-control association analysis.


METHODS
Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services.


METHODS
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.
Green
Elaine K
EK
Department of Psychological Medicine and Biostatics and Bioinformatics Unit, University of Wales College of Medicine, Cardiff.
Raybould
Rachel
R
Macgregor
Stuart
S
Gordon-Smith
Katherine
K
Heron
Jess
J
Hyde
Sally
S
Grozeva
Detelina
D
Hamshere
Marian
M
Williams
Nigel
N
Owen
Michael J
MJ
O'Donovan
Michael C
MC
Jones
Lisa
L
Jones
Ian
I
Kirov
George
G
Craddock
Nick
N
D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D016001:Confidence Intervals; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*
D005819:Genetic Markers; D020890:Neuregulin-1