Support for NRG1 as a susceptibility factor for schizophrenia in a northern Swedish isolated population.
BACKGROUND
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.


METHODS
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.


METHODS
Outpatient and inpatient hospitals.


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


METHODS
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.


CONCLUSIONS
The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.
Alaerts
Maaike
M
Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology, University of Antwerp, B-2610 Antwerp, Belgium.
Ceulemans
Shana
S
Forero
Diego
D
Moens
Lotte N
LN
De Zutter
Sonia
S
Heyrman
Lien
L
Lenaerts
An-Sofie
AS
Norrback
Karl-Fredrik
KF
De Rijk
Peter
P
Nilsson
Lars-Göran
LG
Goossens
Dirk
D
Adolfsson
Rolf
R
Del-Favero
Jurgen
J
D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D013548:Sweden / Q000453:epidemiology; D044465:White People / Q000235:genetics
D005819:Genetic Markers; D020890:Neuregulin-1