title: Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.
abstract: There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.
authors.affiliation: Department of Psychological Medicine, Wales School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK.
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bray
authors.forename: Stanley
authors.initials: S
authors.lastname: Zammit
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
authors.forename: Hywel J
authors.initials: HJ
authors.lastname: Williams
authors.forename: Anna C
authors.initials: AC
authors.lastname: Preece
authors.forename: Sarah
authors.initials: S
authors.lastname: Dwyer
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Wilkinson
authors.forename: Gillian
authors.initials: G
authors.lastname: Spurlock
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.forename: Paul
authors.initials: P
authors.lastname: Buckland
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Aiden P
authors.initials: AP
authors.lastname: Corvin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D020890:Neuregulin-1; D012333:RNA, Messenger; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4