Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population
Chromosome 8p21-12 has been reported to be a susceptibility locus for schizophrenia based on genome-wide linkage scans. After neuregulin 1 (NRG1) was identified as a positional candidate gene for schizophrenia in this locus, several independent association studies have reported controversial results. To determine whether genetic variations in this locus are associated with schizophrenia in the Korean population, we investigated multiplex families and unrelated patients using linkage and association analyses. Seven microsatellite markers in 8p21-12 were genotyped for 40 families with schizophrenia, and a non-parametric linkage analysis was applied. The association study was performed with 242 unrelated schizophrenia patients and the same number of normal controls for three single nucleotide polymorphisms (SNPs), two microsatellite markers and their haplotypes. A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5' end of the first exon of NRG1 for two ("narrow" and "narrow with auditory hallucination (AH)") of the three adopted phenotype classes. In the association study, the G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with AHs. We also found haplotypes which were associated with schizophrenia with a protective effect. This study provides additional suggestive evidence for both the linkage and association of genetic variations on 8p12, a locus of NRG1, with schizophrenia. NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium (LD) with a causal locus of this illness.
Available from: Tim Karl
- "dicates a genetic component , with multiple genes identified . Numerous studies replicated in independent populations have demonstrated that variations in the neuregulin 1 ( NRG1 ) gene increase susceptibility for developing schizophrenia ( Stefansson et al . , 2002 , 2003 ; Williams et al . , 2003 ; Bakker et al . , 2004 ; Corfas et al . , 2004 ; Kim et al . , 2006 ; Walss - Bass et al . , 2006 ) providing strong evidence for an association between the NRG1 gene and schizophrenia ( but also see Sanders et al . , 2008 ) . Furthermore , transcript and protein expression of NRG1 and its receptor v - erb - a erythroblastic leukaemia viral oncogene homologue 4 ( ErbB4 ) are reported to be altered in po"
Available from: Rodney C Go
- "One such line is to perform linkage and/or association studies using population samples from a variety of ancestries. The majority of gene mapping studies to date have targeted samples of European ancestry, yet some linkage and association studies appear to identify risk loci common to only specific ancestral lines, such as neuregulin-1 (NRG1) (Fukui et al 2006; Kim et al 2006; Li et al 2006; Li et al 2004; Stefansson et al 2003; Stefansson et al 2002) or neuregulin-3 (NRG3) (Chen et al 2009). Data from other populations can validate risk loci identified by samples of European ancestry and identify novel risk loci. "
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ABSTRACT: While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.
Available from: Wen-Cheng Xiong
- "Subsequently, NRG1 was shown to reverse LTP and reduce whole-cell NMDA receptor currents in pyramidal neurons of prefrontal cortex, and was also shown to decrease NMDA receptor-mediated EPSCs in prefrontal cortex slices (Gu et al., 2005; Kwon et al., 2005). Interestingly, the NRG1 gene is strongly associated with schizophrenia in diverse populations in Iceland, Scotland, China, Japan, and Korea (Fukui et al., 2006; Kim et al., 2006; Stefansson et al., 2002, 2003; Yang et al., 2003). ErbB4 mRNA is enriched in regions where interneurons are clustered in adult brains (Lai and Lemke, 1991). "
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ABSTRACT: Neuregulin-1 (NRG1), a regulator of neural development, has been shown to regulate neurotransmission at excitatory synapses. Although ErbB4, a key NRG1 receptor, is expressed in glutamic acid decarboxylase (GAD)-positive neurons, little is known about its role in GABAergic transmission. We show that ErbB4 is localized at GABAergic terminals of the prefrontal cortex. Our data indicate a role of NRG1, both endogenous and exogenous, in regulation of GABAergic transmission. This effect was blocked by inhibition or mutation of ErbB4, suggesting the involvement of ErbB4. Together, these results indicate that NRG1 regulates GABAergic transmission via presynaptic ErbB4 receptors, identifying a novel function of NRG1. Because both NRG1 and ErbB4 have emerged as susceptibility genes of schizophrenia, these observations may suggest a mechanism for abnormal GABAergic neurotransmission in this disorder.
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