Schizophrenia Bulletin Advance Access originally published online on August 4, 2005
Schizophrenia Bulletin 2005 31(3):613-617; doi:10.1093/schbul/sbi043
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Association Between the Neuregulin 1 Gene and Schizophrenia: A Systematic Review
Department of Medicine and Public Health, University of Verona, Section of Psychiatry, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy
Division of Psychological Medicine, Institute of Psychiatry, Kings College, London, SE5 8AF
Division of Psychological Medicine, Institute of Psychiatry, Kings College, London, SE5 8AF
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College, London, SE5 8AF
To whom correspondence should be addressed; tel: +39-045 8074441, fax: +39-045 585871, e-mail: stosato{at}mail.univr.it.
Chromosome 8p22–p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAPICE) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same 
300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAPICE association results in about 4,500 subjects is consistent with a small (odds ratio 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAPICE is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.
Keywords: Psychosis / genetic / susceptibility / ggf2 / nrg1 / chromosome 8p
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