Abstract
Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004–April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) β-amyloid (Aβ) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andreasen N, Blennow K (2002) Beta-amyloid (Abeta) protein in cerebrospinal fluid as a biomarker for Alzheimer’s disease. Peptides 23:1205–1214
Andreasen N, Hesse C, Davidsson P, Minthon L, Wallin A, Winblad B, Vanderstichele H, Vanmechelen E, Blennow K (1999) Cerebrospinal fluid beta-amyloid (1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 56:673–680
Bertram L, Tanzi RE (2004) Alzheimer’s disease: one disorder, too many genes? Hum Mol Genet 13(1):R135–R141
Blennow K, Wallin A, Ågren H, Spenger C, Siegfried J, Vanmechelen E (1995) Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer’s disease? Mol Chem Neuropathology 26:231–245
Boguski MS, Lowe TM, Tolstoshev CM (1993) dbEST–database for “expressed sequence tags”. Nat Genet 4:332–333
Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR (1991) Publication bias in clinical research. Lancet 337:867–872
Elkins JS, Douglas VC, Johnston SC (2005) Alzheimer disease risk and genetic variation in ACE: a meta-analysis. Neurology 62:363–368
Emahazion T, Feuk L, Jobs M, Sawyer SL, Fredman D, St Clair D, Prince JA, Brookes AJ (2001) SNP association studies in Alzheimer’s disease highlight problems for complex disease analysis. Trends Genet 17:407–413
Ertekin-Taner N, Ronald J, Asahara H, Younkin L, Hella M, Jain S, Gnida E, Younkin S, Fadale D, Ohyagi Y, Singleton A, Scanlin L, de Andrade M, Petersen R, Graff-Radford N, Hutton M, Younkin S (2003) Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Hum Mol Genet 12:3133–3143
Ertekin-Taner N, Ronald J, Feuk L, Prince J, Tucker M, Younkin L, Hella M, Jain S, Hackett A, Scanlin L, Kelly J, Kihiko-Ehman M, Neltner M, Hersh L, Kindy M, Markesbery W, Hutton M, Andrade M, Petersen RC, Graff-Radford N, Estus S, Brookes AJ, Younkin SG (2005) Elevated amyloid {beta} protein (A{beta}42) and late onset Alzheimer’s disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Hum Mol Genet 14:447–460
Finckh U, van Hadeln K, Muller-Thomsen T, Alberici A, Binetti G, Hock C, Nitsch RM, Stoppe G, Reiss J, Gal A (2003) Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2. Neurogenetics 4:213–217
Goring HH, Terwilliger JD, Blangero J (2001) Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet 69:1357–1369
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309
Johansson A, Hampel H, Faltraco F, Buerger K, Minthon L, Bogdanovic N, Sjogren M, Zetterberg H, Forsell L, Lilius L, Wahlund LO, Rymo L, Prince JA, Blennow K (2003) Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer’s disease and frontotemporal dementia. Neurosci Lett 340:69–73
Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, van Duijn CM, Kehoe PG (2005) Large-scale meta-analysis establishes the association of the ACE indel polymorphism with Alzheimer’s disease. Am J Epidemiol, (in press)
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182
Myers AJ, Marshall H, Holmans P, Compton D, Crook RJ, Mander AP, Nowotny P, Smemo S, Dunstan M, Jehu L, Wang JC, Hamshere M, Morris JC, Norton J, Chakraventy S, Tunstall N, Lovestone S, Petersen R, O’Donovan M, Jones L, Williams J, Owen MJ, Hardy J, Goate A (2004) Variation in the urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD. Am J Med Genet B Neuropsychiatr Genet 124:29–37
Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, Iakovidou V, Maddalena A, Lutjohann D, Ghebremedhin E, Hegi T, Pasch T, Traxler M, Bruhl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock C (2003) Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 60:29–35
Papassotiropoulos A, Tsolaki M, Wollmer MA, Molyva D, Thal DR, Huynh KD, Tracy J, Staehelin HB, Monsch AU, Nitsch RM, Hock C (2005) No association of a non-synonymous PLAU polymorphism with Alzheimer’s disease and disease-related traits. Am J Med Genet B Neuropsychiatr Genet 132B:21–23
Prince JA, Feuk L, Howell WM, Jobs M, Emahazion T, Blennow K, Brookes AJ (2001) Robust and accurate single nucleotide polymorphism genotyping by dynamic allele-specific hybridization (DASH): design criteria and assay validation. Genome Res 11:152–162
Prince JA, Feuk L, Gu HF, Johansson B, Gatz M, Blennow K, Brookes AJ (2003) Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Hum Mutat 22:363–371
Prince JA, Zetterberg H, Andreasen N, Marcusson J, Blennow K (2004) APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. Neurology 62:2116–2118
Pritchard JK, Cox NJ (2002) The allelic architecture of human disease genes: common disease-common variant...or not? Hum Mol Genet 11:2417–2423
Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989
Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169
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 U S A 90:1977–1981
Vanmechelen E, Vanderstichele H (1998) Towards an earlier diagnosis of Alzheimer’s disease. J Biotechnol 66:229–231
Weiss KM, Terwilliger JD (2000) How many diseases does it take to map a gene with SNPs? Nat Genet 26:151–157
Wheeler DL, Church DM, Edgar R, Federhen S, Helmberg W, Madden TL, Pontius JU, Schuler GD, Schriml LM, Sequeira E, Suzek TO, Tatusova TA, Wagner L (2004) Database resources of the National Center for Biotechnology Information: update. Nucleic Acids Res 32(Database issue):D35–40
Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LM, Lutjohann D, Thal D, von Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A (2003) Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer’s disease. Mol Psychiatry 8:635–638
Acknowledgements
Generous financial support was provided by; The Swedish Medical Research Council, Loo and Hans Ostermans Foundation, The Swedish Old Servants Foundation (Gamla Tjänarinnor), Åke Wibergs Foundation, Torsten and Ragnar Söderbergs Foundation, Fredrik and Ingrid Thurings Foundation, Olle Engkvist Byggmästare/Signhild Engkvists Foundation, and Signe and Olof Wallenius Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Blomqvist, M.EL., Reynolds, C., Katzov, H. et al. Towards compendia of negative genetic association studies: an example for Alzheimer disease. Hum Genet 119, 29–37 (2006). https://doi.org/10.1007/s00439-005-0078-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-005-0078-9