Current Psychiatry Reports

, Volume 13, Issue 2, pp 138–146

Power and Pitfalls of the Genome-Wide Association Study Approach to Identify Genes for Alzheimer’s Disease



Until recently, the search for genes contributing to Alzheimer’s disease (AD) had been slow and disappointing, with the notable exception of the APOE ε4 allele, which increases risk and reduces the age at onset of AD in a dose-dependent fashion. Findings from genome-wide association studies (GWAS) made up of fewer than several thousand cases and controls each have not been replicated. Efforts of several consortia—each assembling much larger datasets with sufficient power to detect loci conferring small changes in AD risk—have resulted in robust associations with many novel genes involved in multiple biological pathways. Complex data mining strategies are being used to identify additional members of these pathways and gene–gene interactions contributing to AD risk. Guided by GWAS results, next-generation sequencing and functional studies are under way with the hope of helping us better understand AD pathology and providing new drug targets.


Alzheimer’s disease Genome-wide association study Apolipoprotein E Alzheimer’s disease susceptibility genes 


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

  1. 1.
    Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, et al. A familial Alzheimer’s disease locus on chromosome 1. Science. 1995;269:970–3.PubMedCrossRefGoogle Scholar
  2. 2.
    St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet. 1992;2:330–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science. 1992;258:668–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987;235:880–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376:775–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375:754–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. 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. 1997;278:1349–56.PubMedCrossRefGoogle Scholar
  9. 9.
    Kennedy JL, Farrer LA, Andreasen NC, Mayeux R, St George-Hyslop P. The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science. 2003;302:822–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Ertekin-Taner N. Genetics of Alzheimer disease in the pre- and post-GWAS era. Alzheimers Res Ther. 2010;2:3.PubMedCrossRefGoogle Scholar
  11. 11.
    Pericak-Vance MA, Bebout JL, Gaskell Jr PC, Yamaoka LH, Hung WY, Alberts MJ, et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet. 1991;48:1034–50.PubMedGoogle Scholar
  12. 12.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39:17–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–77.PubMedCrossRefGoogle Scholar
  14. 14.
    Elston RC. Linkage and association. Genet Epidemiol. 1998;15:565–76.PubMedCrossRefGoogle Scholar
  15. 15.
    Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer's disease. Am J Epidemiol. 2005;162:305–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Meng Y, Baldwin CT, Bowirrat A, Waraska K, Inzelberg R, Friedland RP, et al. Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community. Am J Hum Genet. 2006;78:871–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008;105:1620–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Bonnefond A, Froguel P, Vaxillaire M. The emerging genetics of type 2 diabetes. Trends Mol Med. 2010;16:407–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Ghoussaini M, Song H, Koessler T, Al Olama AA, Kote-Jarai Z, Driver KE, et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J Natl Cancer Inst. 2008;100:962–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, 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.PubMedCrossRefGoogle Scholar
  21. 21.
    Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65:45–53.PubMedCrossRefGoogle Scholar
  24. 24.
    Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, et al. A genome-wide association study for late-onset Alzheimer's disease using DNA pooling. BMC Med Genomics. 2008;1:44.PubMedCrossRefGoogle Scholar
  25. 25.
    Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat Genet. 2009;41:192–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Beecham GW, Martin ER, Li YJ, Slifer MA, Gilbert JR, Haines JL, 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.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, et al. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron. 2007;54:713–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Sherva R, Baldwin CT, Inzelberg R, Vardarajan B, Cupples LA, Lunetta K, et al. Identification of novel candidate genes for Alzheimer’s disease by autozygosity mapping using genome wide SNP data from an Israeli-Arab community. J Alzheimers Dis (2010), (Epub ahead of print) PMID: 21098978.Google Scholar
  30. 30.
    Kang DE, Yoon IS, Repetto E, Busse T, Yermian N, Ie L, et al. Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem. 2005;280:31537–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Liang WS, Chen K, Lee W, Sidhar K, Corneveaux JJ, Allen AN, et al. Association between GAB2 haplotype and higher glucose metabolism in Alzheimer’s disease-affected brain regions in cognitively normal APOEepsilon4 carriers. Neuroimage (2010).Google Scholar
  32. 32.
    Naj AC, Beecham GW, Martin ER, Gallins PJ, Powell EH, Konidari I, et al. Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet. 2010;6:e1001130.PubMedCrossRefGoogle Scholar
  33. 33.
    Bowirrat A, Friedland RP, Chapman J, Korczyn AD. The very high prevalence of AD in an Arab population is not explained by APOE epsilon4 allele frequency. Neurology. 2000;55:731.PubMedGoogle Scholar
  34. 34.
    Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–74.PubMedCrossRefGoogle Scholar
  35. 35.
    • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, 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 one of two papers published back to back reporting results from a GWAS of AD in a very large sample composed of datasets from multiple research teams. Genome-wide significant results were obtained for variants in two novel genes whose role in the disorder would not have been predicted from their known functions. This paper demonstrates the importance of having a dataset exceeding 10,000 subjects to detect association with genes conferring a small effect on disease risk.PubMedCrossRefGoogle Scholar
  36. 36.
    • Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, 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 second of two back-to-back papers reporting results from a GWAS of AD in a very large sample composed of datasets from a second consortium of AD genetics researchers. Genome-wide significant results were obtained for variants in two novel genes, one of which (PICALM) was also identified in an independent study.PubMedCrossRefGoogle Scholar
  37. 37.
    Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, et al. Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol (2010), (Epub ahead of print) PMID: 20697030.Google Scholar
  39. 39.
    Huang Y. Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol Med. 2010;16:287–94.PubMedCrossRefGoogle Scholar
  40. 40.
    Danik M, Chabot JG, Hassan-Gonzalez D, Suh M, Quirion R. Localization of sulfated glycoprotein-2/clusterin mRNA in the rat brain by in situ hybridization. J Comp Neurol. 1993;334:209–27.PubMedCrossRefGoogle Scholar
  41. 41.
    Wong P, Pineault J, Lakins J, Taillefer D, Leger J, Wang C, et al. Genomic organization and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis. J Biol Chem. 1993;268:5021–31.PubMedGoogle Scholar
  42. 42.
    May PC, Lampert-Etchells M, Johnson SA, Poirier J, Masters JN, Finch CE. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer’s disease and in response to experimental lesions in rat. Neuron. 1990;5:831–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Calero M, Rostagno A, Matsubara E, Zlokovic B, Frangione B, Ghiso J. Apolipoprotein J (clusterin) and Alzheimer’s disease. Microsc Res Tech. 2000;50:305–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci U S A. 2002;99:10837–42.PubMedCrossRefGoogle Scholar
  45. 45.
    Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, et al. Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron. 2000;27:33–44.PubMedCrossRefGoogle Scholar
  46. 46.
    Sanada K, Gupta A, Tsai LH. Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis. Neuron. 2004;42:197–211.PubMedCrossRefGoogle Scholar
  47. 47.
    Kelly BL, Ferreira A. Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons. Neuroscience. 2007;147:60–70.PubMedCrossRefGoogle Scholar
  48. 48.
    Lambert JC, Grenier-Boley B, Chouraki V, Heath S, Zelenika D, Fievet N, et al. Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis. J Alzheimers Dis. 2010;20:1107–18.PubMedGoogle Scholar
  49. 49.
    Hong MG, Alexeyenko A, Lambert JC, Amouyel P, Prince JA. Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease. J Hum Genet (2010).Google Scholar
  50. 50.
    Jiang X, Barmada MM, Visweswaran S. Identifying genetic interactions in genome-wide data using Bayesian networks. Genet Epidemiol. 2010;34:575–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Medicine (Biomedical Genetics)Boston University School of MedicineBostonUSA
  2. 2.Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Genetics and Genomics, Biostatistics, and EpidemiologyBoston University Schools of Medicine and Public Health, Biomedical Genetics L-320BostonUSA

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