S81INFLUENCES of Polygenic Risk Scores and Schizophrenia Associated CNVS on Broadly and Narrowly Defined Psychoses: Prospective Study and Meta-Analysis (original) (raw)
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Neuroscience and Behavioral Physiology, 2013
One of the most likely candidate genes for schizophrenia is the neuregulin gene NRG1. A number of studies have found linkage of this disease with the 8p12-p21 locus at which this gene is located. Stefansson et al. [20, 21] found an association between schizophrenia and NRG1: carriership of a particular haplotype (HapICE) doubled the risk of developing disease. The HapICE haplotype affects the 5' end of the gene and consists of five oligonucleotide markers and two markers consisting of satellite repeats (478B14-848 and 420M9-1395). Subsequent studies confirmed the association between schizophrenia and NRG1 variants [8, 24]. However, gene polymorphisms and the risk haplotype showed large population-related differences [6, 24] and, despite some progress in seeking the molecular mechanisms of the relationship between this gene and schizophrenia [23], the functional polymorphism explaining the association of NRG1 with the disease remains to be established. This is at least in part related to the complexity of the gene structure and the multiplicity of functions of the protein neuregulin 1. NRG1 is a member of the gene family encoding nerve growth factors. It is one of the most extended human genes and, due to alternative splicing, encodes more than 15 neuregulin 1 isoforms belonging to six families. These isoforms are involved in cell differentiation, proliferation, myelinization, and neuron apoptosis, as well as oligodendrocyte formation. In particular, the major role of neuregulin 1 in neurite growth activation processes is known, affecting immature
Proceedings of the National Academy of Sciences of the United States of America, 2006
Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription ...
The World Journal of Biological Psychiatry, 2010
One important risk gene in schizophrenia is neuregulin-1 (NRG1), which is expressed in different isoforms in the brain. To determine if alterations of NRG1 are present in schizophrenia, we measured gene expression of NRG1 and its main isoforms as well as the impact of genetic variation of NRG1 in an exploratory study examining three brain regions instead of only one as published so far. In all, we examined post-mortem samples from 11 schizophrenia patients and eight normal subjects. We investigated gene expression of total NRG1 and isoforms I, II and III by real-time PCR in the prefrontal cortex (Brodmann areas 9 and 10) and right hippocampal tissue. For the genetic study, we genotyped the NRG1 polymorphism SNP8NRG221533, which is within the core haplotype of the original publication. Compared to controls, gene expression of the NRG1 isoform I was decreased and isoform II increased in the prefrontal cortex (BA10) of schizophrenia patients. There were no statistically significant differences between individuals carrying at least one C allele of SNP8NRG221533 compared to individuals homozygous for the T allele. The decreased expression of NRG1 isoform I and overexpression of isoform II may be related to deficits in receptor function as well as abnormal migration and myelination. However, our study sample was small and results of this exploratory study should be verified in a larger sample.
Translational Psychiatry, 2017
Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5′ and 3′ regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5′-end and two (rs2954041 and rs10503929) near the 3′-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5′ and 3′ e...
Fine Mapping on Chromosome 10q22-q23 Implicates Neuregulin 3 in Schizophrenia
The American Journal of Human Genetics, 2009
Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p ¼ 2 3 10 À5), we performed a peakwide association fine mapping study by using 1414 SNPs across~12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the ''delusion'' factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 3 10 À7. We replicated this association in the collection of 173 unrelated AJ cases (p ¼ 1.55 3 10 À2), with a combined p value of 2.30 3 10 À7. After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p ¼ 2.7 3 10 À3. NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.
Multiple personalities of neuregulin gene family members
The Journal of Comparative Neurology, 2004
In this issue of the Journal, Buonanno and his colleagues delineate important differences between neuregulin 1 (Nrg-1) and neuregulin 2 (Nrg-2). Their study provides intriguing new perspectives on neuregulin signaling mechanisms and the role(s?) of Nrgs in making and maintaining synaptic connections. The neuregulin gene family members are located on distinct chromosomes, with the Nrg-1 and Nrg-2 genes giving rise to multiple isoforms as a result of rich differential splicing. Longart et al. demonstrate dissimilar temporal, spatial, and cellular patterns of expression for Nrg-1 and Nrg-2 in vivo. These results provide a framework for evaluating the Nrg-1 and Nrg-2 signaling systems, which appear perfectly poised to mediate distinct, but perhaps complementary, functions in the formation, maintenance, and plasticity of CNS connections.
Proceedings of the National Academy of Sciences, 2010
Structural and polymorphic variations in Neuregulin 3 ( NRG3 ), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular clo...
Neuregulin-1 genotype is associated with structural differences in the normal human brain
NeuroImage, 2012
The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions.