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Human Molecular Genetics Advance Access originally published online on May 10, 2006
Human Molecular Genetics 2006 15(12):1995-2002; doi:10.1093/hmg/ddl122
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia

Dawei Li1,3, David A. Collier4 and Lin He2,3,*

1Bio-X Center and 2NHGG, Bio-X Center, Shanghai Jiao Tong University, Hao Ran Building, 1954 Hua Shan Road, Shanghai 200030, China, 3Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China and 4Division of Psychological Medicine and MRC Social Genetic and Developmental Psychiatry Centre, The Institute of Psychiatry, King's College, London, UK

* To whom correspondence should be addressed. Tel/Fax: +86 2162822491; Email: helin{at}nhgg.org

Received March 10, 2006; Accepted May 3, 2006

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAPICE), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAPICE. Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 478B14-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR=1.22, 95% CI 1.15–1.3, P=8x10–10). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 478B14-848, 420M9-1395 (haplotype block B), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.


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