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PreprintCited by 35Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

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Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ +447 more·2018·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/294629
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Abstract

Introduction: Late-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.

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  • Large-scale genetic association studies have identified Alzheimer's disease risk variants in a growing list of microglia-related genes.

    “The importance of microglia in Alzheimer’s disease (AD) pathogenesis has been demonstrated by large-scale genetic association studies, which have identified AD risk variants in a growing list of microglia-related genes1–4.”

    From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [1]

  • The SNP rs3740688 is significantly associated with Alzheimer's disease in European populations and is suggested to reduce the risk of developing Alzheimer's disease in that population.

    “Furthermore, the SNPs rs3740688 and rs78245530 are significantly associated with Alzheimer's disease in European [23] and Chinese [24] populations, respectively. Interestingly, these variants are also suggested to reduce the risk of developing Alzheimer's disease in these specific populations [23, 24].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [23]

    The Main Text reports Alzheimer’s disease associations for other named variants, but the available passages do not identify rs3740688 or give an association or protective effect for it. Searches for rs3740688 and for a protective association in Europeans found no passage addressing that SNP; the cited claim therefore cannot be verified from our copy. (LLM, conf=0.72)

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Authors
Kunkle, B., Grenier-Boley, B., Sims, R., Bis, J., Naj, A., Boland, A., Vronskaya, M., van der Lee, S., Amlie-Wolf, A., Bellenguez, C., Frizatti, A., Chouraki, V, Martin, E., Sleegers, K., Badarinarayan, N., Jakobsdottir, J., Hamilton-Nelson, K., Aloso, R., Raybould, R., Chen, Y., Kuzma, A., Hiltunen, M., Morgan, T., Ahmad, S., Vardarajan, B., Epelbaum, J., Hoffmann, P., Boada, M., Beecham, G., Garnier, J., Harold, D., Fitzpatrick, A., Valladares, O., Moutet, M., Gerrish, A., Smith, A., Qu, L., Bacq, D., Denning, N., Jian, X., Zhao, Y., Zompo, M., Fox, N., Grove, M., Choi, S., Mateo, I., Hughes, J., Adams, H., Malamon, J., Garcia, F., Patel, Y., Brody, J., Dombroski, B., Naranjo, M., Daniilidou, M., Eiriksdottir, G., Mukherjee, S., Wallon, D., Uphill, J., Aspelund, T., Cantwell, L., Garzia, F., Galimberti, D., Hofer, E., Butkiewics, M., Fin, B., Scarpini, E., Sarnowski, C., Bush, W., Meslage, S., Kornhuber, J., White, C., Song, Y., Barber, R., Engelborghs, S., Pichler, S., Voijnovic, D., Adams, P., Vandenberghe, R., Mayhaus, M., Cupples, L., Albert, M., De Deyn, P., Gu, W., Himali, J., Beekly, D., Squassina, A., Hartmann, A., Orellana, A., Blacker, D., Rodriguez-Rodriguez, E., Lovestone, S., Garcia, M., Doody, R., Fernadez, C., Sussams, R., Lin, H., Fairchild, T., Benito, Y., Holmes, C., Comic, H., Frosch, M., Thonberg, H., Maier, W., Roschupkin, G., Ghetti, B., Giedraitis, V, Kawalia, A., Li, S., Huebinger, R., Kilander, L., Moebus, S., Hernández, I., Kamboh, M., Brundin, R., Turton, J., Yang, Q., Katz, M., Concari, L., Lord, J., Beiser, A., Keene, C., Helisalmi, S., Kloszewska, I., Kukull, W., Koivisto, A., Lynch, A., Tarraga, L., Larson, E., Haapasalo, A., Lawlor, B., Mosley, T., Lipton, R., Solfrizzi, V, Gill, M., Longstreth, W., Montine, T., Frisardi, V, Ortega-Cubero, S., Rivadeneira, F., Petersen, R., Deramecourt, V, Ciaramella, A., Boerwinkle, E., Reiman, E., Fievet, N., Caltagirone, C., Rotter, J., Reisch, J., Hanon, O., Cupidi, C., Uitterlinden, A., Royall, D., Dufouil, C., Maletta, R., Moreno-Grau, S., Sano, M., Brice, A., Cecchetti, R., St George-Hyslop, P., Ritchie, K., Tsolaki, M., Tsuang, D., Dubois, B., Craig, D., Wu, C., Soininen, H., Avramidou, D., Albin, R., Fratiglioni, L., Germanou, A., Apostolova, L., Keller, L., Koutroumani, M., Arnold, S., Panza, F., Gkatzima, O., Asthana, S., Hannequin, D., Whitehead, P., Atwood, C., Caffarra, P., Hampel, H., Baldwin, C., Lannfelt, L., Rubinsztein, D., Barnes, L., Pasquier, F., Frölich, L., Barral, S., McGuinness, B., Beach, T., Johnston, J., Becker, J., Passmore, P., Bigio, E., Schott, J., Bird, T., Warren, J., Boeve, B., Lupton, M., Bowen, J., Proitsi, P., Boxer, A., Powell, J., Burke, Jr., Kauwe, J., Burns, J., Mancuso, M., Buxbaum, J., Bonuccelli, U., Cairns, N., McQuillin, A., Cao, C., Livingston, G., Carlson, C., Bass, N., Carlsson, C., Hardy, J., Carney, R., Bras, J., Carrasquillo, M., Guerreiro, R., Allen, M., Chui, H., Fisher, E., Cribbs, D., Masullo, C., Crocco, E., DeCarli, C., Bisceglio, G., Dick, M., Ma, L., Duara, R., Graff-Radford, N., Evans, D., Hodges, A., Faber, K., Scherer, M., Fallon, K., Riemenschneider, M., Fardo, D., Heun, R., Farlow, M., Ferris, S., Leber, M., Foroud, T., Heuser, I., Galasko, D., Giegling, I., Gearing, M., Hüll, M., Geschwind, D., Gilbert, Jr., Morris, J., Green, R., Mayo, K., Growdon, J., Feulner, T., Hamilton, R., Harrell, L., Drichel, D., Honig, L., Cushion, T., Huentelman, M., Hollingworth, P., Hulette, C., Hyman, B., Marshall, R., Jarvik, G., Meggy, A., Abner, E., Menzies, G., Jin, L., Leonenko, G., Jun, G., Grozeva, D., Karydas, A., Russo, G., Kaye, J., Kim, R., Jessen, F., Kowall, N., Vellas, B., Kramer, J., Vardy, E., LaFerla, F., Jöckel, K., Lah, J., Dichgans, M., Leverenz, J., Mann, D., Levey, A., Pickering-Brown, S., Lieberman, A., Klopp, N., Lunetta, K., Wichmann, H., Lyketsos, C., Morgan, K., Marson, D., Brown, K., Martiniuk, F., Medway, C., Mash, D., Nöthen, M., Masliah, E., Hooper, N., McCormick, W., Daniele, A., McCurry, S., Bayer, A., McDavid, A., Gallacher, J., McKee, A., van den Bussche, H., Mesulam, M., Brayne, C., Miller, B., Riedel-Heller, S., Miller, C., Miller, J., Al-Chalabi, A., Morris, J., Shaw, C., Myers, A., Wiltfang, J., O’Bryant, S., Coto, E., Olichney, J., Alvarez, V, Parisi, J., Singleton, A., Paulson, H., Collinge, J., Perry, W., Mead, S., Peskind, E., Rosser, M., Pierce, A., Ryan, N., Poon, W., Nacmias, B., Potter, H., Sorbi, S., Quinn, J., Sacchinelli, E., Raj, A., Spalletta, G., Raskind, M., Bossù, P., Reisberg, B., Clarke, R., Reitz, C., Smith, A., Ringman, J., Warden, D., Roberson, E., Wilcock, G., Rogaeva, E., Bruni, A., Rosen, H., Gallo, M., Rosenberg, R., Ben-Shlomo, Y., Sager, M., Mecocci, P., Saykin, A., Pastor, P., Cuccaro, M., Vance, J., Schneider, J., Schneider, L., Seeley, W., Smith, A., Sonnen, J., Spina, S., Stern, R., Swerdlow, R., Tanzi, R., Trojanowski, J., Troncoso, J., Van Deerlin, V., Van Eldik, L., Vinters, H., Vonsattel, J., Weintraub, S., Welsh-Bohmer, K., Wilhelmsen, K., Williamson, J., Wingo, T., Woltjer, R., Wright, C., Yu, C., Yu, L., Alzheimer Disease Genetics Consortium (ADGC), (EADI), T. E. A. D. I., Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Crane, P., Bennett, D., Boccardi, V, De Jager, P., Warner, N., Lopez, O., McDonough, S., Ingelsson, M., Deloukas, P., Cruchaga, C., Graff, C., Gwilliam, R., Fornage, M., Goate, A., Sanchez-Juan, P., Kehoe, P., Amin, N., Ertekin-Taner, N., Berr, C., Debette, S., Love, S., Launer, L., Younkin, S., Dartigues, J., Corcoran, C., Ikram, M., Dickson, D., Campion, D., Tschanz, J., Schmidt, H., Hakonarson, H., Munger, R., Schmidt, R., Farrer, L., Van Broeckhoven, C., O’Donovan, M., DeStefano, A., Jones, L., Haines, J., Deleuze, J., Owen, M., Gudnason, V, Mayeux, R., Escott-Price, V, Psaty, B., Ruiz, A., Ramirez, A., Wang, L., van Duijn, C., Holmans, P., Seshadri, S., Williams, J., Amouyel, P., Schellenberg, G., Lambert, J., & Pericak-Vance, M.
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Corresponding author
Kunkle, BW
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2018-04-04
DOI
10.1101/294629
OpenAlex
W2795847116
Cited by
35
References
119
Citations by year
2025: 4 · 2024: 3 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 6
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Apollo (University of Cambridge) (submittedVersion, other-oa)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Apollo
Funders
  • Alzheimer's Association (U01 AG016976, U01 AG032984, NIRG-11-200110, MNIRG-11-205368)
  • American Federation for Aging Research
  • Brigham Young University
  • University of Pennsylvania (U24‐AG041689, R01AG041797, U24 AG026395, U24 AG026390)
  • University of Washington
  • Wellcome Trust (095317/Z/11/Z)
  • European Commission (2015-2017, FP6-2004-LIFESCIHEALTH-5)
  • Deutsche Forschungsgemeinschaft
  • AXA Research Fund
  • Bundesministerium für Bildung und Forschung (01GI0715, 01GI0429, 01GI0423, 01GI1007A, 01GI0422, 01GS08125, 01GI0712, 01ET1006B, 01GI0711, 01GI0716, 01GI0431, 01GI0713, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B, 01GI0420, 01GI0710, 01GI0714, 01GI0433, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716)
  • Universität des Saarlandes
  • National Institutes of Health (MNIRG-11-205368, 2015-2017, AG016976)
  • Medical Research Council (MR/L501517/1, MR/R024804/1, MR/L010305/1, MC_PC_17112, MR/K013041/1, MR/L023784/1)
  • National Institute on Aging (AG 016976, R01AG042611, U24-AG041689-01, U01AG016976, AG11-380, R01AG011380, U01AG032984, U24 AG21886, R01AG041797, R01AG044546, AG032984, U24AG026395, RC2AG036528, U24AG041689, U24AG021886)
  • National Institute of Neurological Disorders and Stroke (R01NS085419)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
late-onset Alzheimer's disease, genetic susceptibility loci, amyloid-beta processing, APP metabolism, immune system, lipid metabolism, rare variants, ACE, ADAM10, ADAMTS1, genome-wide association study

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