Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify f...
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| Published in: | Nature genetics Vol. 51; no. 3; pp. 414 - 430 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
New York
Nature Publishing Group US
01.03.2019
Nature Publishing Group |
| Subjects: | |
| ISSN: | 1061-4036, 1546-1718, 1546-1718 |
| Online Access: | Get full text |
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| Summary: | Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (
IQCK
,
ACE
,
ADAM10
,
ADAMTS1
,
and
WWOX
), two of which (
ADAM10
,
ACE
) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (
P
= 1.32 × 10
−7
), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism. |
|---|---|
| Bibliography: | ObjectType-Article-1 ObjectType-Evidence Based Healthcare-3 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ADGC. Study design or conception: A.C.N., A.A.-W., E.R.M., K.H.-N., A.B.K., B.N.V., G.W.B., O.V., M.Butkiewicz, W.B., Y.Song, G.D.S., M.A.P.-V. Sample contribution: S.Mukherjee, P.K.C., R.B., P.M.A., M.S.A., D. Beekly, D. Blacker, R.S. Doody, T.J.F., M.P.F., B.Ghetti, R.M.H., M.I.K., M.J.K., C.K., W.K., E.B.L., R.B.L., T.J.M., R.C.P., E.M.R., J.S.R., D.R.R., M. Sano, P.S.G.-H., D.W.T., C.K.W., R.L.A., L.G.A., S.E.A., S.A., C.S.A., C.T.B., L.L.B., S. Barral, T.G.B., J.T.B., E.H.B., T.D.B., B.F.B., J.D.B., A.Boxer, J.R.B., J.M.B., J.D.Buxbaum, N.J.C., C. 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Data generation: B.W.K., K.H.-N., A.B.K., O.V., L.Q., Y.Z., W.P., S.Slifer, J.Malamon, B.A.D., P.W., L.B.C., M.A., M.Tang, J.R.G., L.-S.W. Analysis: B.W.K., A.C.N., A.A.-W., E.R.M., K.H.-N., A.B.K., M.Tang, M.M.C., B.N.V., G.W.B., O.V., M.Butkiewicz, W.B., Y.S., G.D.S., M.A.P.-V. Manuscript preparation: B.W.K., G.D.S., M.A.P.-V. Study supervision/ management: B.W.K., L.A.F., J.Haines, R.Mayeux, L.-S.W., G.D.S., M.A.P.-V. EADI. Study design or conception: P.A., J.-C.L. Sample contribution: K.S., M.Hiltunen, J.E., M.D.Z., I.M., F.S.-G., M.C.D.N., D.Wallon, S.E., R.V., P.D.D., A.Squassina, E.R.-R., C.M.-F., Y.A.B., H.T., V.Giedraitis, L.Kilander, R.Brundin, L.C., S.Helisalmi, A.M.K., A.Haapasalo, V.S., V.Frisardi, V.Deramecourt, N.F., O.H., C.Dufouil, A.Brice, K.R., B.D., H.Soininen, L.Fratiglioni, L.K., F.Panza, D.H., P.C., F.S., P.B., L.Lannfelt, F.P., M.Ingelsson, C.G., P.S.-J., A.L., J.Clarimon, C.Berr, S.D., J.-F.D., A.Pilotto, M.J.B., P.Bosco, E.C., G.N., D.C., C.V.B., P.A., J.-C.L. Data generation: R.O., J.-G.G., M.-L.M., D.Bacq, F.G., B.F., S.Meslage Analysis: B.G.-B., V.D., C.Bellenguez Manuscript preparation: B.G.-B., P.A., J.-C.L. Study supervision/management: J.-F.Deleuze, A.Boland, P.A., J.-C.L. GERAD/ PERADES. Study design or conception: R.Sims, M.C.O., M.J.O., A.R., P.A.H., J.W. Sample contribution: R.Raybould, T.Morgan, P.Hoffmann, D.Harold, O.P., N.D., N.C.F., J.T.H., Y.P., M.Daniilidou, J.U., D.Galimberti, E.Scarpini, J.Kornhuber, S.Sordon., M.Mayhaus, W.G., A.M.H., S.Lovestone, R.Sussams, C.Holmes, W.M., A.Kawalia, S.Moebus, J.Turton, J.Lord, I.K., A.L., B.L., M.Gill, M.D.-F., I.A., A.Ciaramella, C.Cupidi, R.G.M., R.Cecchetti, M.T., D.Craig, D.A., A.G., M.K., O.G., H.Hampel, D.C.R., L.F., B.M., J.A.J., P.Passmore, J.M.S., J.D.W., M.K.L., P.Proitsi, J.Powell, J.S.K.K., M.Mancuso, U.B., A.M., G.Livingston, N.J.B., J.Hardy, J.B., R.Guerreiro, E.F., C.Masullo, G.B., L.M., A.H., M.Scherer, M.Riemenschneider, R.Heun, H.K., M.Leber, I.H., I.G., M.Hull, J.M., K.Mayo, T.F., D.Drichel, T.D.C., P.Hollingworth, R.Marshall, A.Meggy, G.M., G.L., D.G., G.R., F.J., B.V., E.V., K.-H.J., M.Dichgans, D.Mann, S.P.-B., N.K., H.W., K.M., K.Brown, C.Medway, M.M.N., N.M.H., A.Daniele, A.Bayer, J.G., H.V.D.B., C.Brayne, S.R.-H., A.A.-C., C.E.S., J.Wiltfang, V.A., A.B.S., J.C., S.M., M.Rossor, N.S.R., B.N., S.Sorbi, E.S., G.S., C.Caltagirone, M.D.O., R.C., A.D.S., D.W., G.W., A.C.B., M.G., Y.B.-S., P.M., P.P., V.B., N.W., P.D., R.G., P.G.K., S.L., C.C., J.T., R.Munger, A.R., J.W. Data generation: R.Sims, R.Raybould, T.Morgan, P.Hoffmann, D.Harold, A.Gerrish, N.D., P.Hollingworth, R.Marshall, A.Meggy, A.R., J.W. Analysis: R.Sims, M.V., A.F., N.Badarinarayan, D.Harold, G.M., G.L., D.G., V.E.-P., A.R., J.W., P.A.H. Manuscript preparation: R.Sims, T.D.C., P.A.H., J.W. Study supervision/management: R.Sims, L.J., V.E.-P., A.R., P.A.H., J.W. CHARGE. Study design or conception: A.L.D., C.M.V.D., S.S. Sample contribution: J.C.B., A.Ruiz, I.D.R., L.M.R., I.Q., A.C., A.L.F., G.E., J.J.H., A.O., M.E.G., H.L., H.Comic, G.Roschupkin, S.Li, I.Hernández, Q.Y., A.S.B., L.T., T.H.M., WT.L., F.R., E.Boerwinkle, J.I.R., A.G.U., S.M.-G., O.L.L., M.B., M.F., N.A., L.J.L., M.A.I., H.S., R.S., V.G., B.M.P. Data generation: J.C.B., J.Jakobsdottir, A.Ruiz, A.V.S., X.J., S.-H.C., H.H.A., J.A.B., T.A., E.H., C.Sarnowski, D.V., L.A.C. Analysis: J.C.B., S.J.v.d.L., V.C., J.Jakobsdottir, Y.C., Y.Saba, S.Ahmad, A.Ruiz, A.V.S., C.C.W., C.M.V.D., S.S. Manuscript preparation: S.J.v.d.L., A.Ruiz, B.M.P., C.M.V.D., S.S. Study supervision/management: C.M.V.D., S.S. Author contributions |
| ISSN: | 1061-4036 1546-1718 1546-1718 |
| DOI: | 10.1038/s41588-019-0358-2 |