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.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Bertram L, Tanzi RE. Of replications and refutations: the status of Alzheimer’s disease genetic research. Curr Neurol Neurosci Rep. 2001;1:442–50.
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.
Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–74.
Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci. 2008;9:768–78.
Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.
Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest. 2005;115:1449–57.
Cruts M, Van Broeckhoven C. Molecular genetics of Alzheimer’s disease. Ann Med. 1998;30:560–5.
Mardis ER. A decade’s perspective on DNA sequencing technology. Nature. 2011;470:198–203.
•• 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.
• 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.
• 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.
• 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.
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.
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.
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].
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.
Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Clusterin: a forgotten player in Alzheimer’s disease. Brain Res Rev. 2009;61:89–104.
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.
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.
Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68:270–81.
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.
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.
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.
•• 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.
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.
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.
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.
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.
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.
• 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.
Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53.
McClellan J, King M. Genetic heterogeneity in human disease. Cell. 2010;141:210–7.
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.
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.
Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841.
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.
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.
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.
Reiman EM, Webster JA, Myers AJ, et al. GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron. 2007;54:713–20.
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.
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.
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.
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.
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.
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.
• 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.
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.
Seshadri S, Fitzpatrick AL, Ikram MA, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832–40.
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].
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
Corresponding author
Rights 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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11910-011-0193-z