Genetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis Ina Giegling, Just Genius, Jens Benninghoff, Dan Rujescu ⁎ Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstr. 7, 80336 Munich, Germany abstract article info Article history: Received 18 March 2010 Received in revised form 17 June 2010 Accepted 18 June 2010 Available online 1 July 2010 Keywords: Calcium Genetics GWA NMDA Schizophrenia SNP There is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes. © 2010 Elsevier Inc. All rights reserved. 1. Heretability of schizophrenia The mode of inheritance for schizophrenia is complex and non- Mendelian, involving the combined action of several genes (Owen et al., 2009; Williams et al., 2009). The risk of developing the disease increases exponentially with the genetic relatedness to an individual suffering from the disorder. Third-degree relatives carry an approximately 2% risk of developing schizophrenia in comparison with the 1% risk for schizophrenia in the general population, and the risk of 9% in first- degree relatives. Moreover, in monozygotic (MZ) twins, the concordance of schizophrenia rate is approximately 50%. Recently, Lichtenstein et al. (2009) studied 9,009,202 individuals from more than 2 million nuclear families from registries. The risk for schizophrenia was assessed for biological and adoptive parents, offsprings, full-siblings and half-siblings of probands with the disease. First-degree relatives of probands with schizophrenia (n=35,985) were at increased risk. Half-siblings had a significantly increased risk (relative risk [RR] 3.6, 95% CI 2.3–5.5 for maternal half-siblings, and 2.7, 1.9–3.8 for paternal half-siblings), but substantially lower than that of the full-siblings (9.0, 8.5–11.6). In summary Lichtenstein et al. (2009) estimated a heritability for schizophrenia of about 64%. Taken together previous family, twin and adoption studies show that the relative contribution of genetic factors to the etiology of schizophrenia can be estimated to be approximately between 65 and 80% (Cardno et al., 1999; Lichtenstein et al., 2009). 2. Linkage studies From the beginning genetic studies on schizophrenia were based on family studies which were driven by the assumption that genes of major effect can be identified, similar to the highly successful detection of genes with major effects in monogenic diseases. First linkage studies provided e.g. evidence for an involvement of chromosome 5 (Bassett et al., 1988; Sherrington et al., 1988). However, early positive findings were not replicated (Kennedy et al., 1988; St Clair et al., 1989). Nevertheless, Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 1375–1380 Abbreviations: Ca, calcium; CABP, calcium buffering protein; CACNA1C, calcium channel, voltage-dependent; L type, alpha 1C subunit; CI, confidence interval; CNS, central nervous system; DAO, D-amino acid oxidase; DAOA, D-amino acid oxidase activator; DTNBP1, Dysbindin 1, dystrobrevin-binding protein 1; EGFR, epidermal- growth-factor-receptor; ERBB4, v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian; GABA, gamma-aminobutyric-acid; GWA, genome wide association; GWAS, genome wide association study; HLA, human leukocyte antigen; IQ, Intelligence Quotient; ISC, International Schizophrenia Consortium; MAP, mitogen-activated protein; MGS, Molecular Genetics of Schizophrenia Consortium; MK-801, dizocilpine; MZ, monozygotic; NMDA, N-methyl-D-aspartic acid; NO, nitric oxide; NOS1, nitric oxide synthase 1; NRG1, neuregulin 1; NRGN, neurogranin 1; PCP, phenylcyclohex- ylpiperidin; PSD 95, ostsynaptic density protein of 95kDa; RNA, ribonucleic acid; RR, relative risk; SGENE+, Schizophrenia Genetics + consortium; SNP, single nucleotide polymorphism; TCF4, Transcription factor 4; WTCCC, Wellcome Trust Case-Control Consortium. ⁎ Corresponding author.Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstr. 7, 80336 München, Germany. Tel.: + 49 89 5160 5756; fax: + 49 89 5160 5779. E-mail address: Dan.Rujescu@med.uni-muenchen.de (D. Rujescu). 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.06.018 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp