Two NOTCH4 polymorphisms and their relation to schizophrenia susceptibility and different personality traits.
BACKGROUND
Recently, linkage disequilibrium mapping of the major histocompatibility complex region on the short arm of human chromosome 6 suggested that the NOTCH4 locus is highly associated with schizophrenia.


OBJECTIVE
We analysed two polymorphisms in this gene in Swedish schizophrenic patients ( =74) and control subjects ( =135). The NOTCH4 variants were also analysed in schizophrenic patients with regard to subdiagnosis, age at first hospitalization, abuse/dependence of alcohol, solvents, or drugs, previous suicide attempts, extrapyramidal symptoms, treatment with anticholinergic drugs, and response to anti-psychotic drug treatment. Control subjects were scrutinized with regard to personality, another partially heritable trait suggested being of importance in schizophrenia. In addition, two intermediate endophenotypes suggested being of importance in schizophrenia, dopamine D(2) receptor density in striatum and monoamine metabolites in cerebrospinal fluid, respectively, were investigated with regard to the two NOTCH4 variants.


RESULTS
There was no significant association between the patients and the controls for the two investigated polymorphisms neither for the parameters analysed in the schizophrenia material. The NOTCH4 SNP2 variant, an A-->G substitution, was associated with the Karolinska Scales of Personality Irritability scale. The NOTCH4 (CTG)(n) variant was associated with the revised NEO personality inventory Extraversion and Activity (E4) scales. However, after correction for multiple testing, no difference remained significant. The results for the endophenotypes and the polymorphisms were non-significant.


CONCLUSIONS
The present study does not support that the investigated NOTCH4 variants have a major influence on susceptibility to schizophrenia or related neurobiological traits.
Carmine
Andrea
A
Department of Neuroscience, Clinical Neurogenetics Unit, Stockholm, Sweden.
Chheda
Milan G
MG
Jönsson
Erik G
EG
Sedvall
Göran C
GC
Farde
Lars
L
Gustavsson
J Petter
JP
Bergman
Hans
H
Anvret
Maria
M
Buervenich
Silvia
S
Olson
Lars
L
D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid; D004198:Disease Susceptibility; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010551:Personality / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics*; D011795:Surveys and Questionnaires; D013548:Sweden; D014055:Tomography, Emission-Computed; D044465:White People
D015306:Biogenic Monoamines; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch