1. ¹Dr Einar Martens' Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
2. ²Department of Clinical Medicine, Bergen Mental Health Research Center, University of Bergen, Bergen, Norway
3. ³Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps University, Marburg, Germany
4. ⁴Department of Psychiatry and Psychotherapy, Philipps University, Marburg, Germany
5. ⁵Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany
6. ⁶Department of Child and Adolescent Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany
7. ⁷Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

Correspondence: Dr S Le Hellard, Dr Einar Martens' Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021, Bergen, Norway. E-mail: stephanie.le.hellard@helse-bergen.no

Received 19 August 2007; Revised 5 October 2007; Accepted 8 October 2007; Published online 15 January 2008.

Abstract

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1 and INSIG2) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (P=0.0003–0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.