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Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer’s disease

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Abstract

Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer’s disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1, and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052–0.062). This research suggests a recessive component to the etiology of LOAD.

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References

  1. Gibson J, Morton NE, Collins A (2006) Extended tracts of homozygosity in outbred human populations. Hum Mol Genet 15:789–795. doi:ddi493

    Article  PubMed  CAS  Google Scholar 

  2. Li L, Ho S, Chen C, Wei C, Wong W et al (2006) Long contiguous stretches of homozygosity in the human genome. Hum Mutat 27:1115–1121. doi:10.1002/humu.20399

    Article  PubMed  CAS  Google Scholar 

  3. McQuillan R, Leutenegger A, Abdel-Rahman R, Franklin CS, Pericic M et al (2008) Runs of homozygosity in European populations. Am J Hum Genet 83:359–372. doi:10.1016/j.ajhg.2008.08.007

    Article  PubMed  CAS  Google Scholar 

  4. Devilee P, Cleton-Jansen AM, Cornelisse CJ (2001) Ever since Knudson. Trends Genet 17:569–573. doi:11585662

    Article  PubMed  CAS  Google Scholar 

  5. Raghavan M, Lillington DM, Skoulakis S, Debernardi S, Chaplin T et al (2005) Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 65:375–378. doi:65/2/375

    PubMed  CAS  Google Scholar 

  6. Woods CG, Valente EM, Bond J, Roberts E (2004) A new method for autozygosity mapping using single nucleotide polymorphisms (SNPs) and EXCLUDEAR. J Med Genet 41:e101. doi:15286161

    Article  PubMed  CAS  Google Scholar 

  7. Simon-Sanchez J, Scholz S, Fung H, Matarin M, Hernandez D et al (2007) Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum Mol Genet 16:1–14. doi:ddl436

    Article  PubMed  CAS  Google Scholar 

  8. Clarimón J, Djaldetti R, Lleó A, Guerreiro RJ, Molinuevo JL et al (2008) Neurobiol Aging . doi:S0197-4580(08)00055-9

    Google Scholar 

  9. Leutenegger A, Prum B, Génin E, Verny C, Lemainque A et al (2003) Estimation of the inbreeding coefficient through use of genomic data. Am J Hum Genet 73:516–523. doi:12900793

    Article  PubMed  CAS  Google Scholar 

  10. Rademakers R, Cruts M, Van Broeckhoven C (2003) Genetics of early-onset Alzheimer dementia. Scientific World Journal 3:497–519. doi:12847300

    PubMed  CAS  Google Scholar 

  11. Bertram L, Tanzi RE (2004) Alzheimer’s disease: one disorder, too many genes. Hum Mol Genet 13(Spec No 1):R135–R141. doi:14764623

    Article  PubMed  CAS  Google Scholar 

  12. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472. doi:8350998

    PubMed  CAS  Google Scholar 

  13. van Duijn CM, de Knijff P, Cruts M, Wehnert A, Havekes LM et al (1994) Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease. Nat Genet 7:74–78. doi:8075646

    Article  PubMed  Google Scholar 

  14. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923. doi:8346443

    Article  PubMed  CAS  Google Scholar 

  15. Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD et al (2003) Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum Mol Genet 12:415–422. doi:12566388

    Article  PubMed  CAS  Google Scholar 

  16. Liu F, Arias-Vásquez A, Sleegers K, Aulchenko YS, Kayser M et al (2007) A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet 81:17–31. doi:S0002-9297(07) 62813-4

    Article  PubMed  CAS  Google Scholar 

  17. Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T et al (2007) GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron 54:713–720. doi:S0896-6273(07) 00379-0

    Article  PubMed  CAS  Google Scholar 

  18. Gibbs JR, Singleton A (2006) Application of genome-wide single nucleotide polymorphism typing: simple association and beyond. PLoS Genet 2:e150. doi:06-PLGE-RV-0291R2

    Article  PubMed  Google Scholar 

  19. Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959

    PubMed  CAS  Google Scholar 

  20. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320. doi:10.1038/nature04226

    Article  Google Scholar 

  21. Lencz T, Lambert C, DeRosse P, Burdick KE, Morgan TV et al (2007) Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. Proc Natl Acad Sci USA 104:19942–1997. doi:0710021104

    Article  PubMed  CAS  Google Scholar 

  22. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23. doi:ng1934

    Article  PubMed  CAS  Google Scholar 

  23. Hamilton G, Proitsi P, Jehu L, Morgan A, Williams J et al (2007) Candidate gene association study of insulin signaling genes and Alzheimer’s disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci. Am J Med Genet B Neuropsychiatr Genet 144B:508–516. doi:10.1002/ajmg.b.30503

    Article  PubMed  CAS  Google Scholar 

  24. Webber KM, Stocco DM, Casadesus G, Bowen RL, Atwood CS et al (2006) Steroidogenic acute regulatory protein (StAR): evidence of gonadotropin-induced steroidogenesis in Alzheimer disease. Mol Neurodegener 1:14. doi:1750-1326-1-14

    Article  PubMed  Google Scholar 

  25. Li X, Alafuzoff I, Soininen H, Winblad B, Pei J (2005) Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J 272:4211–4220. doi:EJB4833

    Article  PubMed  CAS  Google Scholar 

  26. Meyers DS, Skwish S, Dickinson KE, Kienzle B, Arbeeny CM (1997) Beta 3-adrenergic receptor-mediated lipolysis and oxygen consumption in brown adipocytes from cynomolgus monkeys. J Clin Endocrinol Metab 82:395–401. doi:9024225

    Article  PubMed  CAS  Google Scholar 

  27. Hoyer S (2004) Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications. Adv Exp Med Biol 541:135–152. doi:14977212

    PubMed  CAS  Google Scholar 

  28. Craft S, Watson GS (2004) Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 3:169–178. doi:14980532

    Article  PubMed  CAS  Google Scholar 

  29. Sugawara T, Holt JA, Kiriakidou M, Strauss JF (1996) Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (StAR) gene. Biochemistry 35:9052–9059. doi:8703908

    Article  PubMed  CAS  Google Scholar 

  30. Proud CG (2002) Regulation of mammalian translation factors by nutrients. Eur J Biochem 269:5338–5349. doi:12423332

    Article  PubMed  CAS  Google Scholar 

  31. Yu C, Seltman H, Peskind ER, Galloway N, Zhou PX et al (2007) Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer’s disease: patterns of linkage disequilibrium and disease/marker association. Genomics 89:655–665. doi:S0888-7543(07) 00050-X

    Article  PubMed  CAS  Google Scholar 

  32. Bowirrat A, Friedland RP, Chapman J, Korczyn AD (2000) The very high prevalence of AD in an Arab population is not explained by APOE epsilon4 allele frequency. Neurology 55:731. doi:10980749

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (Z01 AG000950-06) and the Portuguese Fundacao para a Ciencia e Tecnologia grants (SFRH/BD/29647/2006 and SFRH/BD/27442/2006). The experiments presented here comply with the current laws of the United States of America. The authors would like to thank the Translational Genomics Research Institute (TGen), in particular Dr. Eric Reiman and collaborators for publicly releasing the data that made this study possible.

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Authors and Affiliations

  1. Molecular Genetics Section and Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A1014, 35 Convent Drive, Bethesda, MD, 20892, USA

    M. A. Nalls, R. J. Guerreiro, J. Simon-Sanchez, J. T. Bras, J. R. Gibbs & A. B. Singleton

  2. Center for Neurosciences and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, 3004-504, Portugal

    R. J. Guerreiro & J. T. Bras

  3. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    B. J. Traynor

  4. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, 20892, USA

    L. Launer

  5. Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    J. Hardy

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  1. M. A. Nalls
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  2. R. J. Guerreiro
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  3. J. Simon-Sanchez
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  4. J. T. Bras
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  5. B. J. Traynor
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  6. J. R. Gibbs
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  7. L. Launer
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  8. J. Hardy
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  9. A. B. Singleton
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Correspondence to A. B. Singleton.

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M. A. Nalls and R. J. Guerreiro contributed equally to this work.

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Nalls, M.A., Guerreiro, R.J., Simon-Sanchez, J. et al. Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer’s disease. Neurogenetics 10, 183–190 (2009). https://doi.org/10.1007/s10048-009-0182-4

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  • DOI: https://doi.org/10.1007/s10048-009-0182-4

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