title: Neuregulin 1 and susceptibility to schizophrenia.
abstract: The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.
authors.affiliation: deCODE Genetics, Reykjavik, Iceland. kstefans@decode.is.
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Engilbert
authors.initials: E
authors.lastname: Sigurdsson
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Steinthorsdottir
authors.forename: Soley
authors.initials: S
authors.lastname: Bjornsdottir
authors.forename: Thordur
authors.initials: T
authors.lastname: Sigmundsson
authors.forename: Shyamali
authors.initials: S
authors.lastname: Ghosh
authors.forename: Jon
authors.initials: J
authors.lastname: Brynjolfsson
authors.forename: Steinunn
authors.initials: S
authors.lastname: Gunnarsdottir
authors.forename: Omar
authors.initials: O
authors.lastname: Ivarsson
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Chou
authors.forename: Omar
authors.initials: O
authors.lastname: Hjaltason
authors.forename: Birgitta
authors.initials: B
authors.lastname: Birgisdottir
authors.forename: Helgi
authors.initials: H
authors.lastname: Jonsson
authors.forename: Vala G
authors.initials: VG
authors.lastname: Gudnadottir
authors.forename: Elsa
authors.initials: E
authors.lastname: Gudmundsdottir
authors.forename: Asgeir
authors.initials: A
authors.lastname: Bjornsson
authors.forename: Brynjolfur
authors.initials: B
authors.lastname: Ingvarsson
authors.forename: Andres
authors.initials: A
authors.lastname: Ingason
authors.forename: Sigmundur
authors.initials: S
authors.lastname: Sigfusson
authors.forename: Hronn
authors.initials: H
authors.lastname: Hardardottir
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Donna
authors.initials: D
authors.lastname: Lai
authors.forename: Mingdong
authors.initials: M
authors.lastname: Zhou
authors.forename: Daniela
authors.initials: D
authors.lastname: Brunner
authors.forename: Vincent
authors.initials: V
authors.lastname: Mutel
authors.forename: Acuna
authors.initials: A
authors.lastname: Gonzalo
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.forename: Jesus
authors.initials: J
authors.lastname: Sainz
authors.forename: Gardar
authors.initials: G
authors.lastname: Johannesson
authors.forename: Thorkell
authors.initials: T
authors.lastname: Andresson
authors.forename: Daniel
authors.initials: D
authors.lastname: Gudbjartsson
authors.forename: Andrei
authors.initials: A
authors.lastname: Manolescu
authors.forename: Michael L
authors.initials: ML
authors.lastname: Frigge
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gulcher
authors.forename: Hannes
authors.initials: H
authors.lastname: Petursson
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000235:genetics*; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D020890:Neuregulin-1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4