Skip to main content

Advertisement

SpringerLink
Log in

NRG3 gene is associated with the risk and age at onset of Alzheimer disease

  • Neurology and Preclinical Neurological Studies - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Alzheimer’s-Association, Thies W, Bleiler L (2011) Alzheimer’s disease facts and figures. Alzheimer’s Dement 7(2):208–244. doi:10.1016/j.jalz.2011.02.004

  • Anton ES, Ghashghaei HT, Weber JL, McCann C, Fischer TM, Cheung ID, Lai C (2004) Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat Neurosci 7(12):1319–1328. doi:10.1038/nn1345

    Article  CAS  PubMed  Google Scholar 

  • Assimacopoulos S, Grove EA, Ragsdale CW (2003) Identification of a Pax6-dependent epidermal growth factor family signaling source at the lateral edge of the embryonic cerebral cortex. J Neurosci 23(16):6399–6403

    CAS  PubMed  Google Scholar 

  • Avramopoulos D, Wang R, Valle D, Fallin MD, Bassett SS (2007) A novel gene derived from a segmental duplication shows perturbed expression in Alzheimer’s disease. Neurogenetics 8(2):111–120. doi:10.1007/s10048-007-0081-5

    Article  CAS  PubMed  Google Scholar 

  • Balciuniene J, Feng N, Iyadurai K, Hirsch B, Charnas L, Bill BR, Selleck SB (2007) Recurrent 10q22–q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 80(5):938–947. doi:10.1086/513607

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265. doi:10.1093/bioinformatics/bth457

    Article  CAS  PubMed  Google Scholar 

  • Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, Graff-Radford NR (2009) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet 41(2):192–198. doi:10.1038/ng.305

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carteron C, Ferrer-Montiel A, Cabedo H (2006) Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival. J Cell Sci 119(Pt 5):898–909. doi:10.1242/jcs.02799

    Article  CAS  PubMed  Google Scholar 

  • Donix M, Small GW, Bookheimer SY (2012) Family history and APOE-4 genetic risk in Alzheimer’s disease. Neuropsychol Rev 22(3):298–309. doi:10.1007/s11065-012-9193-2

    Article  PubMed Central  PubMed  Google Scholar 

  • Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66(2):87–98. doi:10.1159/000119108

    Article  PubMed Central  PubMed  Google Scholar 

  • Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Pulver AE (2003) Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 73(3):601–611. doi:10.1086/378158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278(16):1349–1356

    Article  CAS  PubMed  Google Scholar 

  • Filippini N, Rao A, Wetten S, Gibson RA, Borrie M, Guzman D, Matthews PM (2009) Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer’s disease. Neuroimage 44(3):724–728. doi:10.1016/j.neuroimage.2008.10.003

    Article  PubMed  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296(5576):2225–2229. doi:10.1126/science.1069424

    Article  CAS  PubMed  Google Scholar 

  • Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Pedersen NL (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63(2):168–174. doi:10.1001/archpsyc.63.2.168

    Article  PubMed  Google Scholar 

  • Harrison PJ, Tunbridge EM (2008) Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33(13):3037–3045. doi:10.1038/sj.npp.1301543

    Article  CAS  PubMed  Google Scholar 

  • Heinzen EL, Need AC, Hayden KM, Chiba-Falek O, Roses AD, Strittmatter WJ, Goldstein DB (2010) Genome-wide scan of copy number variation in late-onset Alzheimer’s disease. J Alzheimers Dis 19(1):69–77. doi:10.3233/JAD-2010-1212

    PubMed Central  PubMed  Google Scholar 

  • Hollingworth P, Harold D, Jones L, Owen MJ, Williams J (2011) Alzheimer’s disease genetics: current knowledge and future challenges. Int J Geriatr Psychiatry 26(8):793–802. doi:10.1002/gps.2628

    Article  PubMed  Google Scholar 

  • Hollingworth P, Sweet R, Sims R, Harold D, Russo G, Abraham R, Williams J (2012) Genome-wide association study of Alzheimer’s disease with psychotic symptoms. Mol Psychiatry 17(12):1316–1327. doi:10.1038/mp.2011.125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ivleva EI, Morris DW, Moates AF, Suppes T, Thaker GK, Tamminga CA (2010) Genetics and intermediate phenotypes of the schizophrenia—bipolar disorder boundary. Neurosci Biobehav Rev 34(6):897–921. doi:10.1016/j.neubiorev.2009.11.022

    Article  CAS  PubMed  Google Scholar 

  • Kao WT, Wang Y, Kleinman JE, Lipska BK, Hyde TM, Weinberger DR, Law AJ (2010) Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. Proc Natl Acad Sci USA 107(35):15619–15624. doi:10.1073/pnas.1005410107

    Article  CAS  PubMed  Google Scholar 

  • Lambert JC, Amouyel P (2011) Genetics of Alzheimer’s disease: new evidences for an old hypothesis? Curr Opin Genet Dev 21(3):295–301. doi:10.1016/j.gde.2011.02.002

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R (2008) Analyses of the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study: implication of additional loci. Arch Neurol 65(11):1518–1526. doi:10.1001/archneur.65.11.1518

    Article  PubMed Central  PubMed  Google Scholar 

  • Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Roses AD (2008) Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 65(1):45–53. doi:10.1001/archneurol.2007.3

    Article  PubMed  Google Scholar 

  • Liu F, Arias-Vasquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, van Duijn CM (2007) A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet 81(1):17–31. doi:10.1086/518720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, Gibbs RA (2010) Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 362(13):1181–1191. doi:10.1056/NEJMoa0908094

    Article  CAS  PubMed  Google Scholar 

  • Lutz MW, Crenshaw DG, Saunders AM, Roses AD (2010) Genetic variation at a single locus and age of onset for Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc 6(2):125–131. doi:10.1016/j.jalz.2010.01.011

    Article  CAS  Google Scholar 

  • Marchini J, Cardon LR, Phillips MS, Donnelly P (2004) The effects of human population structure on large genetic association studies. Nat Genet 36(5):512–517. doi:10.1038/ng1337

    Article  CAS  PubMed  Google Scholar 

  • Meier S, Strohmaier J, Breuer R, Mattheisen M, Degenhardt F, Mühleisen TW, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Wüst S (2013) Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder. Int J Neuropsychopharmacol 16(3):549–556. doi:10.1017/S1461145712000697

    Google Scholar 

  • Morar B, Dragovic M, Waters FA, Chandler D, Kalaydjieva L, Jablensky A (2011) Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Mol Psychiatry 16(8):860–866. doi:10.1038/mp.2010.70

    Article  CAS  PubMed  Google Scholar 

  • Piacentini S, Polimanti R, Squitti R, Mariani S, Migliore S, Vernieri F, Fuciarelli M (2012) GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer’s disease: association hypothesis for an uncommon genetic variant. Neurosci Lett 506(2):203–207. doi:10.1016/j.neulet.2011.11.005

    Article  CAS  PubMed  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. doi:10.1086/519795

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reisberg H, Ferris SH, Sclan SG (1993) Empirical evaluation of the global deterioration scale for staging Alzheimer’s disease. Am J Psychiatry 150(4):680–682

    CAS  PubMed  Google Scholar 

  • Reitz C, Cheng R, Schupf N, Lee JH, Mehta PD, Rogaeva E, Mayeux R (2012) Association between variants in IDE-KIF11-HHEX and plasma amyloid beta levels. Neurobiol Aging 33(1):199 e113–199 e197. doi:10.1016/j.neurobiolaging.2010.07.005

    Google Scholar 

  • Rogers BS, Lippa CF (2012) A clinical approach to early-onset inheritable dementia. Am J Alzheimers Dis Other Demen 27(3):154–161. doi:10.1177/1533317512444000

    Article  PubMed  Google Scholar 

  • Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90(20):9649–9653

    Article  CAS  PubMed  Google Scholar 

  • Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Haussler D (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15(8):1034–1050. doi:10.1101/gr.3715005

    Article  CAS  PubMed  Google Scholar 

  • Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90(5):1977–1981

    Article  CAS  PubMed  Google Scholar 

  • Sweet RA, Nimgaonkar VL, Devlin B, Lopez OL, DeKosky ST (2002) Increased familial risk of the psychotic phenotype of Alzheimer disease. Neurology 58(6):907–911

    Article  CAS  PubMed  Google Scholar 

  • Sweet RA, Bennett DA, Graff-Radford NR, Mayeux R, National Institute on Aging Late-Onset Alzheimer’s Disease Family Study, Group (2010) Assessment and familial aggregation of psychosis in Alzheimer’s disease from the National Institute on Aging Late Onset Alzheimer’s Disease Family Study. Brain 133(Pt 4):1155–1162. doi:10.1093/brain/awq001

    Article  PubMed  Google Scholar 

  • Thompson PM, Mega MS, Woods RP, Zoumalan CI, Lindshield CJ, Blanton RE, Toga AW (2001) Cortical change in Alzheimer’s disease detected with a disease-specific population-based brain atlas. Cereb Cortex 11(1):1–16

    Article  CAS  PubMed  Google Scholar 

  • Twine NA, Janitz K, Wilkins MR, Janitz M (2011) Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer’s disease. PLoS One 6(1):e16266. doi:10.1371/journal.pone.0016266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Uhlhaas PJ, Singer W (2006) Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 52(1):155–168. doi:10.1016/j.neuron.2006.09.020

    Article  CAS  PubMed  Google Scholar 

  • Wu L, Rosa-Neto P, Hsiung GY, Sadovnick AD, Masellis M, Black SE, Gauthier S (2012) Early-onset familial Alzheimer’s disease (EOFAD). Can J Neurol Sci 39(4):436–445

    PubMed  Google Scholar 

  • Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Godowski PJ (1997) Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci USA 94(18):9562–9567

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN, 37614-1700, USA

    Ke-Sheng Wang, Nuo Xu & Liang Wang

  2. Department of Family Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX, USA

    Lorenzo Aragon & Radu Ciubuc

  3. Department of Psychiatry and Neurology and the Center of Excellence in Neuroscience, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX, USA

    Tania Bedard Arana, Leonora Petty, David Briones, Cynthia Camarillo, Michael A. Escamilla & Chun Xu

  4. University of Toronto, Toronto, ON, Canada

    ChunXiang Mao

  5. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, The People’s Republic of China

    Brenda Bin Su

  6. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06520, USA

    Xingguang Luo

Authors
  1. Ke-Sheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nuo Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorenzo Aragon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Radu Ciubuc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tania Bedard Arana
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. ChunXiang Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leonora Petty
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David Briones
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Brenda Bin Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xingguang Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Cynthia Camarillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael A. Escamilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ke-Sheng Wang or Chun Xu.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, KS., Xu, N., Wang, L. et al. NRG3 gene is associated with the risk and age at onset of Alzheimer disease. J Neural Transm 121, 183–192 (2014). https://doi.org/10.1007/s00702-013-1091-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-013-1091-0

Keywords

Search

Navigation