Evidence for a negative association between schizophrenia and a polymorphism in the insulin receptor substrate-3 (IRS-3) gene.
OBJECTIVE
Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin and insulin-like growth factor signalling in cells might underlie changes in both brain and body in schizophrenia. In this regard, the insulin receptor substrates 1-4, linking both the insulin and insulin-like growth factor-1 receptors with intracellular pathways, might be of interest to study genetically. In the present study, we chose to study the insulin receptor substrate-3 (IRS-3) gene as a candidate gene in schizophrenia.


METHODS
The IRS-3 gene of 93 patients with the diagnosis of schizophrenia according to DSM-IV criteria and 57 healthy control subjects was screened for DNA sequence variations, followed by case-control analyses of total 10 detected polymorphisms.


RESULTS
The A/G genotype of the single nucleotide polymorphism (SNP) rs117078492 in the IRS-3 gene occurred in 5.3% of the control subjects compared with in 0% of the patients (p=0.05). Similarly, the haplotypes 5 and 3X, constructed from polymorphisms in the IRS-3 gene and including the A allele of this A/G SNP, occurred only in the control subjects and not in the patients (5.3% vs 0%, p=0.05).


CONCLUSIONS
Our findings suggest that individuals carrying the A allele of this A/G SNP in the IRS-3 gene as well as the estimated haplotypes 5 or 3X including this A allele, have a protection against schizophrenia development.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Kristina.Melkersson@ki.se
Kristina
K
Melkersson
Bengt
B
Persson
D000328:Adult; D016022:Case-Control Studies; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
C491585:IRS3P protein, human; D055504:Insulin Receptor Substrate Proteins