BRIEF RESEARCH COMMUNICATION Risk Variants in the S100B Gene Predict Elevated S100B Serum Concentrations in Healthy Individuals Christa Hohoff, 1 * Gerald Ponath, 1 Christine M. Freitag, 2,3 Florian K€ astner, 1 Petra Krakowitzky, 4 Katharina Domschke, 1 Katja Koelkebeck, 1 Frank Kipp, 5 Christof von Eiff, 5,6 J€ urgen Deckert, 1,7 and Matthias Rothermundt 1 1 Department of Psychiatry, University of Muenster, Muenster, Germany 2 Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Germany 3 Department of Child and Adolescent Psychiatry, Goethe-University of Frankfurt, Frankfurt, Germany 4 Institute of Transfusion Medicine, University of Muenster, Muenster, Germany 5 Institute of Medical Microbiology, University of Muenster, Muenster, Germany 6 Wyeth Pharma GmbH, Muenster, Germany 7 Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany Received 11 November 2008; Accepted 18 February 2009 Several lines of evidence suggest an important role of the S100B protein and its coding gene in different neuropathological and psychiatric disorders like dementia, bipolar affective disorders and schizophrenia. To clarify whether a direct link exists between gene and gene product, that is, whether S100B variants directly modulate S100B serum concentration, 196 healthy individuals were assessed for S100B serum concentrations and genotyped for five potentially functional S100B SNPs. Functional variants of the serotonergic genes 5-HT1A and 5-HTT possibly modulating S100B serum levels were also studied. Further, publicly available human postmortem gene expression data were re-analyzed to elucidate the impact of S100B, 5-HT1A and 5-HTT SNPs on frontal cortex S100B mRNA expression. Several S100B SNPs, particularly rs9722, and the S100B haplotype T-G-G-A (including rs2186358-rs11542311-rs2300403-rs9722) were asso- ciated with elevated S100B serum concentrations (Bonferroni corrected P < 0.05). Of these, rs11542311 was also associated with S100B mRNA expression directly (Bonferroni corrected P ¼ 0.05) and within haplotype G-A-T-C (rs11542311- rs2839356-rs9984765-rs881827; P ¼ 0.004), again with the G- allele increasing S100B expression. Our results suggest an im- portant role of S100B SNPs on S100B serum concentrations and S100B mRNA expression. It hereby links recent evidence for both, the impact of S100B gene variation on various neurological or psychiatric disorders like dementia, bipolar affective dis- orders and schizophrenia and the strong relation between S100B serum levels and these disorders. Ó 2009 Wiley-Liss, Inc. Key words: S100 calcium binding protein B; functional poly- morphisms; mRNA expression; postmortem frontal cortex; association S100B as a member of the S100 calcium-binding protein super- family is an acidic protein with a molecular weight of 21 kDa and exists as a homodimer composed of two b subunits. It is highly abundant in the human brain, primarily in glia, where it exerts paracrine and autocrine effects on neurons, glia, and microglia. S100B is supposed to play an important role in calcium homeo- stasis, signal transduction, cell proliferation and differentiation, cellular energy metabolism and cytoskeletal modification [Donato, 2001; Heizmann et al., 2002]. Further, a potential role of S100B- RAGE interactions in S100B neurotrophic and neurotoxic effects is assumed [Donato, 2007]. Therefore, S100B is involved in the regulation of degenerative and regenerative processes in the central nervous system [Rothermundt et al., 2003; Sen and Belli, 2007]. Additional Supporting Information may be found in the online version of this article. C. Hohoff and G. Ponath contributed equally to this work. *Correspondence to: Christa Hohoff, Ph.D., Department of Psychiatry, University of Muenster, Albert-Schweitzer-Strasse 11, 48149 Muenster, Germany. E-mail: hohoffch@uni-muenster.de Published online 27 March 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.b.30950 How to Cite this Article: Hohoff C, Ponath G, Freitag CM, K€ astner F, Krakowitzky P, Domschke K, Koelkebeck K, Kipp F, von Eiff C, Deckert J, Rothermundt M. 2010. Risk Variants in the S100B Gene Predict Elevated S100B Serum Concentrations in Healthy Individuals. Am J Med Genet Part B 153B:291–297. Ó 2009 Wiley-Liss, Inc. 291 Neuropsychiatric Genetics