NRG3 gene is associated with the risk and age at onset of Alzheimer disease
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The Neuregulin 3 (NRG3) gene at 10q22–q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer’s disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G–C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A–G haplotype from rs504522 and rs474018 as well as the A–G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10−5). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case–control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.
KeywordsAlzheimer disease Age at onset NRG3 gene Single-nucleotide polymorphisms
We acknowledge the NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype data and DNA samples from his/her original study and the primary funding organization that supported the contributing study “Multi-Site Collaborative Study for Genotype–Phenotype Associations in Alzheimer’s disease and longitudinal follow-up of Genotype–Phenotype Associations in Alzheimer’s disease and Neuroimaging component of Genotype–Phenotype Associations in Alzheimer’s disease” and “National Institute on Aging—Late Onset Alzheimer’s Disease Family Study: Genome-Wide Association Study for Susceptibility Loci”. The genotypic and associated phenotypic data used in the study, “Multi-Site Collaborative Study for Genotype–Phenotype Associations in Alzheimer’s Disease (GenADA)” were provided by the GlaxoSmithKline, R&D Limited. The datasets used for analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219.v1.p1. Funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease” was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer’s Disease includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer’s Disease. The datasets used for analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000168.v1.p1.
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