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An α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease

Nature Genetics volume 22, pages 19–21 (1999)Cite this article

Blacker et al.1 reported an association between Alzheimer disease (AD) and the deletion allele (A2M*2) of an intronic polymorphism in the α-2-macroglobulin gene (A2M; ref. 2 ), which confers a risk for AD (OR=3.55, 95% CI=1.90-7.03) comparable with that of APOE*E4 (OR=3.54, 95% CI=1.76-7.12). We analysed two independent sets of AD families3,4 using the same family-based association (sibship disequilibrium test1 (SDT) and sib transmission-disequilibrium test5 (S-TDT)) methods. Following the scheme of Blacker et al.1, we limited these analyses to nuclear families of European descent in which all affected individuals had AD onset over 50 years, marker information was available for at least one unaffected sib and, in the case of the S-TDT, two or more distinct genotypes were present in the sibship. We averaged P values for the S-TDT over 100 iterations (10,000 replicates per iteration) using a Monte-Carlo method6. Both data sets demonstrated the association of AD and APOE*E4 (SDT, Duke, P=0.000007; Toronto, P=0.0009), indicating sufficient power to detect associations of the magnitude reported for A2M*2 (ref. 1). Although prior evidence shows that these pedigrees are enriched for an AD locus on chromosome 12 near A2M (Refs 3, 7), we were unable to detect an association with the A2M*2 polymorphism using either the SDT or S-TDT, even when the "stringent unaffecteds" method1 was applied (SDT, Duke, n = 60, P = 0.80, Toronto, n = 45, P = 0.82; S-TDT, Duke, n = 17, P = 0.64, Toronto, n = 21, P = 0.75). Furthermore, we did not detect an association in two independent series of sporadic AD cases of European descent after adjustment for APOE*E4 status (Table 1), despite the fact that each data set had more than 80% power to detect an odds ratio as low as 1.87 (an effect much smaller than reported for A2M*2; ref. 1).

Table 1 A2M allele and genotype frequencies among sporadic AD cases and controls
Full size table

Blacker et al. analysed 104 sibships from the NIMH data set1, but we investigated an overlapping set of 143 NIMH sibships that met the same selection criteria1. Analysis of this larger data set generated marginal or non-significant results (SDT, n=143, P=0.08; S-TDT, n=59, P=0.05). Furthermore, these results derive almost entirely from the subset of sibships collected at a single institution, NIMH site 3 (SDT, n=56, P=0.03; S-TDT, n=20, P=0.04). The lack of a trend towards an association in sibships from NIMH sites 1 (SDT, n=46, P=1.0; S-TDT, n=19, P=0.85) and 2 (SDT, n=41, P=0.65; S-TDT, n=20, P=0.53), together with the robust association with APOE*E4 ( P<0.0009) in all three NIMH sub-data sets, indicates that the results for sites 1 and 2 are not due to reduced statistical power.

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Figure 1: No difference in molecular weight or abundance of A2M transcript and A2M protein monomer in A2M*2 carriers.

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Acknowledgements

Supported by: federal grants AG09029 (L.A.F.), NS31153 (M.A.P.-V., J.L.H.) and AG05128 (A.D.R., A.S., D.S.); a LEAD award for excellence in Alzheimer disease (A.D.R.); a T.L. Temple award (M.A.P.-V.) and grants RG2-96044 (M.A.P.-V.) and RG2-96051 (J.L.H.) from the Alzheimer Association; the Medical Research Council of Canada, Canadian Genetic Diseases Network, Alzheimer Association of Ontario, Howard Hughes Medical Research Foundation, EJLB Foundation (P.H.St.G.-H.); FWO-Vlaanderen, NFWO-Lotto, VLAB/IWT, the 4th Framework EEC-Biotechnology program and by the Rooms-fund (F.V.L.); Peterborough Burgess Fellowship (E.A.R.); Uehara Memorial Foundation and Japan Society for the Promotion of Science (T.K.); and a fellowship from NIH grant T32-AG00115 (S.P.).

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Author notes

  1. Ekaterina A. Rogaeva, Smita Premkumar and Janet Grubber: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Centre for Research in Neurodegenerative Diseases, University of Toronto,

    Ekaterina A. Rogaeva, Toshitaka Kawarai, Youqiang Song, Gang Yu, Antonio Orlacchio, York Pei, Masaki Nishimura, Agres Supala & Peter H. St. George-Hyslop

  2. Department of Medicine (Division of Neurology), The Toronto Hospital, Toronto, Ontario, Canada

    Ekaterina A. Rogaeva, Toshitaka Kawarai, Youqiang Song, Gang Yu, Antonio Orlacchio, York Pei, Masaki Nishimura, Agres Supala & Peter H. St. George-Hyslop

  3. Genetics Program, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA

    Smita Premkumar & Lindsay A. Farrer

  4. Departments of Medicine, Neurology, and Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA

    Lindsay A. Farrer

  5. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

    Janet Grubber, William K. Scott, De'Lisa M. Hill, Suzanne M. Abou-Donia, Eden R. Martin, Ann M. Saunders, Allen D. Roses, Donald Schmechel, Alison Crane-Gatherum & Margaret A. Pericak-Vance

  6. Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA

    Janet Grubber, William K. Scott, De'Lisa M. Hill, Suzanne M. Abou-Donia, Eden R. Martin, Jeffrey J. Vance & Margaret A. Pericak-Vance

  7. Bryan Alzheimer Disease Research Center, Duke University Medical Center, Durham, North Carolina, USA

    Ann M. Saunders, Allen D. Roses, Donald Schmechel & Fred Van Leuven

  8. Experimental Genetics Group, Center for Human Genetics, Flanders Institute for Biotechnology, Leuven, Belgium

    Lutgarde Serneels

  9. Hamilton Regional Laboratory Medicine Program, McMaster University Medical Center, Hamilton, Ontario, Canada

    Brenda Roberge

  10. Department of Neurology and Psychiatry, University of Florence, Firenze, Italy

    Sandro Sorbi

  11. Centro Regionale di Neurogenetica ASL 6, Lamezia Terme, Italy

    Amalia Bruni

  12. Department of Psychiatry and Behavioral Sciences, Neuropsychiatric Institute, Alzheimer's Disease Center,

    Gary W. Small

  13. Center on Aging, University of California at Los Angeles, California, USA

    Gary W. Small

  14. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA

    P. Michael Conneally

  15. Program in Human Genetics and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA

    Jonathan L. Haines

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  1. Ekaterina A. Rogaeva
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Correspondence to Lindsay A. Farrer.

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Rogaeva, E., Premkumar, S., Grubber, J. et al. An α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. Nat Genet 22, 19–21 (1999). https://doi.org/10.1038/8729

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