Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population

ArticleinAmerican Journal of Medical Genetics Part B Neuropsychiatric Genetics 141B(3):281-6 · April 2006with9 Reads
DOI: 10.1002/ajmg.b.30209 · Source: PubMed
Abstract
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.
    • "Much research indicates 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., 2002Stefansson et al., , 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 postmortem schizophrenia brain (Hashimoto et al., 2004; Law et al., 2006 Law et al., , 2007 Chong et al., 2008; Barakat et al., 2010; Marballi et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: The neuregulin1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic NMDA, dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus Nrg1(+/-) mice exhibited age dependent alterations in NMDA receptors. Nrg1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old Nrg1(+/-) mice compared to control littermates of the same age (12%; p=0.026), an effect that was not seen in 20-week old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week-old Nrg1(+/-) mice compared to control littermates of the same age (14%; p=0.011). Nrg1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts.
    Full-text · Article · Jun 2013
    • "Much research indicates 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., 2002Stefansson et al., , 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 postmortem schizophrenia brain (Hashimoto et al., 2004; Law et al., 2006 Law et al., , 2007 Chong et al., 2008; Barakat et al., 2010; Marballi et al., 2012). "
    Full-text · Article · Jun 2013
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · May 2009
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