Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population

Abstract

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. To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population. 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. Outpatient and inpatient hospitals. A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population. Association between markers and disease. 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. The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.