Support for involvement of neuregulin 1 in schizophrenia pathophysiology.
Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.
Petryshen
T L
TL
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Middleton
F A
FA
Kirby
A
A
Aldinger
K A
KA
Purcell
S
S
Tahl
A R
AR
Morley
C P
CP
McGann
L
L
Gentile
K L
KL
Rockwell
G N
GN
Medeiros
H M
HM
Carvalho
C
C
Macedo
A
A
Dourado
A
A
Valente
J
J
Ferreira
C P
CP
Patterson
N J
NJ
Azevedo
M H
MH
Daly
M J
MJ
Pato
C N
CN
Pato
M T
MT
Sklar
P
P
D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020890:Neuregulin-1 / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011174:Portugal / Q000453:epidemiology; D012016:Reference Values; D012559:Schizophrenia / Q000208:ethnology* / Q000235:genetics*; D044465:White People / Q000235:genetics
C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1