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Maaike Alaerts, PhD; Shana Ceulemans, MSc; Diego Forero, MD; Lotte N. Moens, PhD; Sonia De Zutter, BE; Lien Heyrman, MSc; An-Sofie Lenaerts, BA; Karl-Fredrik Norrback, MD; Peter De Rijk, PhD; Lars-Göran Nilsson, MD; Dirk Goossens, PhD; Rolf Adolfsson, MD; Jurgen Del-Favero, PhD

Arch Gen Psychiatry. 2009;66(8):828-837.

Context  Neuregulin 1 (NRG1), a growth factor involved in neurodevelopment, myelination, neurotransmitter receptor expression, and synaptic plasticity, first joined the list of candidate genes for schizophrenia when a 7-marker haplotype at the 5' end of the gene (Hap_ICE) was shown to be associated with the disorder in the Icelandic population. Since then, more genetic and functional evidence has emerged, which supports a role for NRG1 in the development of schizophrenia.

Objective  To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population.

Design  Detailed linkage disequilibrium (LD)–based patient-control association study. This is the first study to type and analyze the 7 Hap_ICE markers and a set of 32 HapMap tagging single-nucleotide polymorphisms (SNPs) that represents variants with a minor allele frequency of at least 1% and fully characterizes the LD structure of the 5' part of NRG1.

Setting  Outpatient and inpatient hospitals.

Participants  A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population.

Main Outcome Measures  Association between markers and disease.

Results  Analysis of the Hap_ICE markers showed the association of a 7-marker and 2-microsatellite haplotype, different from the haplotypes associated in the Icelandic population and overrepresented in northern Swedish control individuals. Subsequently, a more detailed analysis that included all 37 genotyped SNPs was performed by investigating haplotypic association, dependent and independent of LD block structure. We found significant association with 5 SNPs located in the second intron of NRG1 (.007  P  .04). Also, 2-, 3-, and 4-SNP windows that comprise these SNPs were associated (P < 3 x 10^–4). One protective haplotype (0% vs 1.8%; P <5 x 10^–5) and 1 disease risk–causing haplotype (40.4% vs 34.9%, P = .02) were defined.

Conclusion  The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.

Author Affiliations: Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology and University of Antwerp, Belgium (Drs Alaerts, Forero, Moens, Norrback, De Rijk, Nilsson, Goosens, Adolfsson, and Del-Favero, and Mss Ceulemans, De Zutter, Heyrman, Lenaerts); Department of Clinical Sciences, Psychiatry, Umeå University and Department of Psychiatry, Hospital of Sunderby, Luleå (Drs Norrback and Adolfsson); and Department of Psychology, Stockholm University, Sweden (Dr Nilsson).

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