Lack of association to a NRG1 missense polymorphism in schizophrenia or bipolar disorder in a Costa Rican population

Abstract

A missense polymorphism in the NRG1 gene, Val > Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val > Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n = 358), schizophrenia (SZ, n = 273), or unrelated controls (CO, n = 479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val > Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study.

Investigation of Epistasis Between DAOA and 5HTR1A Variants on Clinical Outcomes in Patients with Schizophrenia

“…Additionally, the positive association found in our previous studies (Chiesa et al, 2011;Crisafulli et al, 2012) may not have been sufficiently robust to yield an interaction effect between the two SNPs. Similar findings have been presented in other studies as well (Andreasen et al, 2012;Moon et al, 2011).…”

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…However, there are more studies reporting increased mRNA levels of NRG1 Type I , II , and IV in the PFC and/or hippocampus of autopsy material from SZ patients (Hashimoto et al, 2004; Law et al, 2006; Parlapani et al, 2010; Weickert et al, 2012) as well as in neurons derived from induced pluripotent stem cells of SZ patients (Brennand and Gage, 2012). Increases in Type I and IV mRNA relate to SNP8NRG221132 and SNP8NRG243177, respectively (Law et al, 2006; Moon et al, 2011). The picture for Type III expression is less clear.…”

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…They reported an increased expression of type I NRG1 was associated with the rare A allele of SNP8NRG221132 (rs73235619) among controls but not those with schizophrenia and an increase in type IV expression associated with the T allele of SNP8NRG243177 (rs6994992) in both those with schizophrenia and controls Moon et al 2011;Tan et al 2007). The latter association has been replicated in vitro (Tan et al, 2007) and the SNP8NRG243177 T allele has also been linked to lower levels of Ig-NRG1 immunoreactivity in serum (Shibuya et al 2010) but replication of Law et al's ) initial eQTL findings in independent human brain tissue has yet to be reported.…”