Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia

Nadine Norton, Valentina Escott-Price, Derek W. Morris, Nicholas John Bray, Stanley Zammit, Nigel Melville Williams, Hywel John Williams, Anna Charlotte Preece, Sarah Dwyer, Jennifer C. Wilkinson, Gillian Spurlock, George Kirov, Paul Robert Buckland, John L. Waddington, Michael Gill, Aiden P. Corvin, Michael John Owen, Michael John O'Donovan

Research output: Contribution to journalArticle (Academic Journal)peer-review

153 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)96-101
Number of pages6
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume141B
Issue number1
DOIs
Publication statusPublished - 2006

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