Abstract
We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10−13) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10−15).
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Acknowledgements
This work was done in collaboration with Illumina. The authors are grateful to the participants and their relatives. We also thank the staff and researchers at the Krókháls recruitment center, the Memory Clinic at the National Hospital of Iceland and the deCODE Genetics core facilities. This work was carried out with support from the Academy of Finland; EVO grant 5772708 of Kuopio University Hospital; the Strategic Funding of the University on Eastern Finland (University of Eastern Finland–Brain); the Sigrid Juselius Foundation; Framework Programme 7, grant agreement 601055; VPH Dementia Research Enabled by IT VPH-DARE@IT; the Research Council of Norway (223273, 225989, 237250/EU JPND); the K.G. Jebsen Foundation; the Norwegian Health Association; the AXA Research Fund, the Fondation Université Pierre et Marie Curie and the Fondation pour la Recherche sur Alzheimer, Paris, France; and the program 'Investissements d'Avenir' ANR-10-IAIHU-06.
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S.S., H. Stefansson, T.J. and K.S. designed the study. S.S., H.J., A.I., H. Helgason, P.S., S.A.G., A.K. and U.U. carried out data analysis. O.T.M. performed experiments. S.H., H. Soininen, M.H., DemGene, D.A., T.F., I.D.U., S.D., S.B.S., L.R.W., G.-P.K., L.T.W., G.S., O.A.A., J.J.L., A.I.L., I.G., H. Hampel, D.R., P.V.J., S.B. and J.S. diagnosed and recruited patients. S.S., H. Stefansson, T.J. and K.S. wrote the manuscript with the support of the remaining authors.
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S.S., H. Stefansson, T.J., H.J., A.I., H. Helgason, P.S., O.T.M., S.A.G., U.U., A.K. and K.S. are employed by deCODE Genetics/Amgen.
Integrated supplementary information
Supplementary Figure 1 ABCA7 transcripts at the exon 41 border in a c.5570+5G>C carrier and a c.5570+5G>C non-carrier.
Coordinates are NCBI Build 36. The c.5570+5G>C carrier and non-carrier are shown in the upper and lower panels, respectively.
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Supplementary Figure 1, Supplementary Note and Supplementary Tables 1–5. (PDF 980 kb)
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Steinberg, S., Stefansson, H., Jonsson, T. et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nat Genet 47, 445–447 (2015). https://doi.org/10.1038/ng.3246
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DOI: https://doi.org/10.1038/ng.3246
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