Association study of Neuregulin-1 gene polymorphisms in a north Indian schizophrenia sample

C.B. Patel Research Centre, Vile Parle (West), Mumbai, India.
Schizophrenia Research (Impact Factor: 3.92). 01/2013; 144(1-3). DOI: 10.1016/j.schres.2012.12.017
Source: PubMed


Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population.

NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls).

Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p≤0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336-rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively.

Suggestive associations with SZ and SZ-related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation.

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Available from: Prachi Kukshal,
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    • "Overall, dozens of SNPs of NRG1 have been associated with schizophrenia, both at 5 0 (Kukshal et al. 2013; Benzel et al. 2007; Corvin et al. 2004; Hall et al. 2004; Petryshen et al. 2005; Stefansson et al. 2002; Zhao et al. 2004) and 3 0 regions (Bakker et al. 2004; Benzel et al. 2007; Lachman et al. 2006; Li et al. 2004; Petryshen et al. 2005). Recently, genome-wide association studies (GWAS) for schizophrenia have also reported a nominal association between several SNPs in NRG1 gene and schizophrenia, with p values spanning from 1.59 9 10 -5 for rs4316112 to 1.38 9 10 -3 for rs10095694 (Athanasiu et al. 2010; Shi et al. 2009). "
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    ABSTRACT: Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5′ end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.
    NeuroMolecular Medicine 08/2014; 16(4). DOI:10.1007/s12017-014-8323-9 · 3.68 Impact Factor
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    • "We attempted to examine the effect of DTNBP1 (rs1011313) and NRG1 (rs35753505) polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects recruited from South India. From amongst several SNPs of the NRG1 and DTNBP1genes that have been reported to be significantly associated with schizophrenia (Funke et al., 2004; Yang, 2012), we chose the, above-mentioned SNPs of DTNBP1 and NRG1 genes, as they have been shown by previous haplotype analysis and association studies to be core markers of schizophrenia (Bray et al., 2005; Kukshal et al., 2013; Nawaz et al., 2013; Pae et al., 2008; Prata et al., 2009). Surprisingly, however, no previous study has examined the relationship between the above SNPs and brain volumes. "
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    ABSTRACT: Multiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N = 38) and healthy subjects (N = 37) from South India. Patients with schizophrenia showed trend-level (p < 0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia.
    Asian Journal of Psychiatry 08/2014; 10. DOI:10.1016/j.ajp.2014.04.002
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