Skip to main content

Advertisement

Log in

Alzheimer’s Genetics in the GWAS Era: A Continuing Story of ‘Replications and Refutations’

Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

After a decade of intensive investigation but only few replicable results, Alzheimer’s disease (AD) genetics research is slowly picking up pace. This is mostly owing to the completion of several genome-wide association studies (GWAS), which have suggested the existence of over three dozen potential new AD susceptibility genes. Although only a handful of these could be confirmed in subsequent independent replication efforts to date, this success rate is still much higher than in the pre-GWAS era. This review provides a brief summary of the principal methodologic advances in genetics research of the past decade, followed by a description of the most compelling findings that these advances have unearthed in AD. The paper closes with a discussion of the persistent methodologic difficulties and challenges and an outlook on what we can expect to gain from the next 10 years of AD genetics research.

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

Access this article

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

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bertram L, Tanzi RE. Of replications and refutations: the status of Alzheimer’s disease genetic research. Curr Neurol Neurosci Rep. 2001;1:442–50.

    Article  PubMed  CAS  Google Scholar 

  2. Bertram L, McQueen MB, Mullin K, et al. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39:17–23.

    Article  PubMed  CAS  Google Scholar 

  3. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–74.

    Article  PubMed  Google Scholar 

  4. Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci. 2008;9:768–78.

    Article  PubMed  CAS  Google Scholar 

  5. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.

    Article  PubMed  CAS  Google Scholar 

  6. Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest. 2005;115:1449–57.

    Article  PubMed  CAS  Google Scholar 

  7. Cruts M, Van Broeckhoven C. Molecular genetics of Alzheimer’s disease. Ann Med. 1998;30:560–5.

    Article  PubMed  CAS  Google Scholar 

  8. Mardis ER. A decade’s perspective on DNA sequencing technology. Nature. 2011;470:198–203.

    Article  PubMed  CAS  Google Scholar 

  9. •• Durbin RM, Abecasis GR, Altshuler DL, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–73. This is the release of pilot data from the “1000 Genomes Project” that eventually aims at providing whole-genome sequences for 1000 individuals from multiple ethnic backgrounds; once completed, this project will vastly facilitate all aspects of human genetics research.

    Article  PubMed  CAS  Google Scholar 

  10. • Bilgüvar K, Oztürk AK, Louvi A, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010;467:207–10. This is one of the first projects applying massively parallel sequencing to identify novel mutations causing a Mendelian disorder.

    Article  PubMed  Google Scholar 

  11. • Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–3. This is one of the first projects applying massively parallel sequencing to identify novel mutations causing a Mendelian disorder.

    Article  PubMed  CAS  Google Scholar 

  12. • Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010;362:1181–91. This is one of the first projects applying massively parallel sequencing to identify novel mutations causing a Mendelian disorder.

    Article  PubMed  CAS  Google Scholar 

  13. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9:356–69.

    Article  PubMed  CAS  Google Scholar 

  14. Shatunov A, Mok K, Newhouse S, et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 2010;9:986–94.

    Article  PubMed  CAS  Google Scholar 

  15. International Parkinson’s Disease Genetics Consortium: Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21292315. [Accessed February 20, 2011].

  16. Strittmatter WJ, Saunders AM, Schmechel D, et al. 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. 1993;90:1977–81.

    Article  PubMed  CAS  Google Scholar 

  17. Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Clusterin: a forgotten player in Alzheimer’s disease. Brain Res Rev. 2009;61:89–104.

    Article  PubMed  CAS  Google Scholar 

  18. Jones L, Harold D, Williams J. Genetic evidence for the involvement of lipid metabolism in Alzheimer’s disease. Biochim Biophys Acta. 2010;1801:754–61.

    PubMed  CAS  Google Scholar 

  19. Carter CJ. APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle. Neurosci Lett. 2010;483:96–100.

    Article  PubMed  CAS  Google Scholar 

  20. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68:270–81.

    Article  PubMed  CAS  Google Scholar 

  21. Zetzsche T, Rujescu D, Hardy J, Hampel H. Advances and perspectives from genetic research: development of biological markers in Alzheimer’s disease. Expert Rev Mol Diagn. 2010;10:667–90.

    Article  PubMed  CAS  Google Scholar 

  22. Schjeide BM, Schnack C, Lambert J, et al. The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. Arch Gen Psychiatry. 2011;68:207–13.

    Article  PubMed  CAS  Google Scholar 

  23. Ku CS, Loy EY, Pawitan Y, Chia KS. The pursuit of genome-wide association studies: where are we now? J Hum Genet. 2010;55:195–206.

    Article  PubMed  CAS  Google Scholar 

  24. •• Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52. This is a landmark paper demonstrating the extreme polygenic nature of schizophrenia, a classic genetically complex disease.

    PubMed  CAS  Google Scholar 

  25. Lill CM, Tanzi RE, Bertram L. Genetics of Neurodegenerative Diseases. In Basic Neurochemistry, Eighth Edition: Molecular, Cellular and Medical Aspects. Edited by Siegel GJ, Albers RW, Brady S, Price D. Elsevier Publishing; in press.

  26. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:973–7.

    Article  PubMed  CAS  Google Scholar 

  27. Lleó A, Blesa R, Queralt R, et al. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002;59:1759–63.

    Article  PubMed  Google Scholar 

  28. Raux G, Guyant-Maréchal L, Martin C, et al. Molecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update. J Med Genet. 2005;42:793–5.

    Article  PubMed  CAS  Google Scholar 

  29. Van Deerlin VM, Sleiman PMA, Martinez-Lage M, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010;42:234–9.

    Article  PubMed  Google Scholar 

  30. • Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41:1088–93. This is the first GWAS in AD to imply CLU and PICALM as potential AD susceptibility loci, both of which can now be considered established.

    Article  PubMed  CAS  Google Scholar 

  31. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53.

    Article  PubMed  CAS  Google Scholar 

  32. McClellan J, King M. Genetic heterogeneity in human disease. Cell. 2010;141:210–7.

    Article  PubMed  CAS  Google Scholar 

  33. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361:1651–61.

    Article  PubMed  CAS  Google Scholar 

  34. Rovelet-Lecrux A, Hannequin D, Raux G, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38:24–6.

    Article  PubMed  CAS  Google Scholar 

  35. Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841.

    Article  PubMed  CAS  Google Scholar 

  36. Heinzen EL, Need AC, Hayden KM, et al. Genome-wide scan of copy number variation in late-onset Alzheimer’s disease. J Alzheimers Dis. 2010;19:69–77.

    PubMed  Google Scholar 

  37. Grupe A, Abraham R, Li Y, et al. Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet. 2007;16:865–73.

    Article  PubMed  CAS  Google Scholar 

  38. Coon KD, Myers AJ, Craig DW, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry. 2007;68:613–8.

    Article  PubMed  CAS  Google Scholar 

  39. Reiman EM, Webster JA, Myers AJ, et al. GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron. 2007;54:713–20.

    Article  PubMed  CAS  Google Scholar 

  40. Li H, Wetten S, Li L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65:45–53.

    Article  PubMed  Google Scholar 

  41. Poduslo SE, Huang R, Huang J, Smith S. Genome screen of late-onset Alzheimer’s extended pedigrees identifies TRPC4AP by haplotype analysis. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:50–5.

    Article  PubMed  CAS  Google Scholar 

  42. Abraham R, Moskvina V, Sims R, et al. A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC Med Genomics. 2008;1:44.

    Article  PubMed  Google Scholar 

  43. Bertram L, Lange C, Mullin K, et al. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008;83:623–32.

    Article  PubMed  CAS  Google Scholar 

  44. Beecham GW, Martin ER, Li Y, et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009;84:35–43.

    Article  PubMed  CAS  Google Scholar 

  45. Carrasquillo MM, Zou F, Pankratz VS, et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet. 2009;41(2):192–8.

    Article  PubMed  CAS  Google Scholar 

  46. • Lambert J, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41:1094–9. This is the first GWAS in AD to imply CLU and CR1 as potential AD susceptibility loci, both of which can now be considered established.

    Article  PubMed  CAS  Google Scholar 

  47. Potkin SG, Guffanti G, Lakatos A, et al. Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease. PLoS ONE. 2009;4:e6501.

    Article  PubMed  Google Scholar 

  48. Seshadri S, Fitzpatrick AL, Ikram MA, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832–40.

    Article  PubMed  CAS  Google Scholar 

  49. Naj AC, Beecham GW, Martin ER, et al. Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet. 2010;6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20885792. [Accessed February 21, 2011].

Download references

Acknowledgments

This work was sponsored by funding from the Cure Alzheimer Fund, the Michael J. Fox Foundation for Parkinson’s Research, and the German Federal Ministry for Education and Research (BMBF). L. Bertram was financially supported by funds from the Deutsche Forschungsgemeinschaft (DFG).

Disclosure

No potential conflict of interest relevant to this article was reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lars Bertram.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bertram, L. Alzheimer’s Genetics in the GWAS Era: A Continuing Story of ‘Replications and Refutations’. Curr Neurol Neurosci Rep 11, 246–253 (2011). https://doi.org/10.1007/s11910-011-0193-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-011-0193-z

Keywords

Navigation