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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Nature Genetics (2019) | Download Citation

Abstract

Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

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Acknowledgements

This work was funded by the Netherlands Organization for Scientific Research (NWO VICI 453-14-005). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO: 480-05-003), by the VU University, Amsterdam, the Netherlands, and by the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services SurfSARA. The work was also funded by the Research Council of Norway (grant nos. 251134, 248778, 223273, 213837, and 225989), KG Jebsen Stiftelsen, the Norwegian Health Association, European Community’s JPND Program, ApGeM RCN grant no. 237250, and the European Community’s grant no. PIAPP-GA-2011-286213 PsychDPC. This research has been conducted using the UK Biobank resource under application number 16406 and the public ADSP data set, obtained through the Database of Genotypes and Phenotypes under accession number phs000572. Full acknowledgments for the studies that contributed data can be found in the Supplementary Note. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data.

Author information

Author notes

  1. These authors contributed equally: I.E. Jansen, J.E. Savage.

  2. These authors jointly supervised this work: S. Ripke, O.A. Andreassen, D. Posthuma.

Affiliations

  1. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands

    • Iris E. Jansen
    • , Jeanne E. Savage
    • , Kyoko Watanabe
    • , Sven Stringer
    • , Christiaan de Leeuw
    •  & Danielle Posthuma
  2. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands

    • Iris E. Jansen
    •  & Wiesje M. van der Flier
  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Julien Bryois
    • , Dylan M. Williams
    • , Ida K. Karlsson
    • , Sara Hägg
    • , Patrick F. Sullivan
    •  & Nancy L. Pedersen
  4. deCODE Genetics/Amgen, Reykjavik, Iceland

    • Stacy Steinberg
    • , Hreinn Stefansson
    •  & Kari Stefansson
  5. Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN, USA

    • Julia Sealock
  6. Institute of Gerontology and Aging Research Network–Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden

    • Ida K. Karlsson
  7. NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Lavinia Athanasiu
    • , Aree Witoelar
    • , Francesco Bettella
    • , Srdjan Djurovic
    • , Yunpeng Wang
    •  & Ole A. Andreassen
  8. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Lavinia Athanasiu
  9. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Nicola Voyle
    • , Petroula Proitsi
    • , Dag Aarsland
    •  & Richard Dobson
  10. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Aree Witoelar
    • , Francesco Bettella
    • , Yunpeng Wang
    •  & Ole A. Andreassen
  11. Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway

    • Dag Aarsland
  12. Department of Neurology, Akershus University Hospital, Lørenskog, Norway

    • Ina S. Almdahl
    •  & Tormod Fladby
  13. AHUS Campus, University of Oslo, Oslo, Norway

    • Ina S. Almdahl
    •  & Tormod Fladby
  14. Department of Psychiatry of Old Age, Oslo University Hospital, Oslo, Norway

    • Ina S. Almdahl
  15. Department of Community Medicine, University of Tromsø, Tromsø, Norway

    • Fred Andersen
  16. Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway

    • Sverre Bergh
    • , Anne Brækhus
    •  & Geir Selbæk
  17. Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway

    • Sverre Bergh
  18. Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland

    • Sigurbjorn Bjornsson
    • , Palmi V. Jonsson
    •  & Jon Snaedal
  19. Geriatric Department, Oslo University Hospital, Oslo, Norway

    • Anne Brækhus
  20. Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway

    • Geir Bråthen
    • , Ingvild Saltvedt
    • , Sigrid B. Sando
    •  & Linda R. White
  21. Department of Neurology, St Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway

    • Geir Bråthen
    • , Sigrid B. Sando
    •  & Linda R. White
  22. Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA

    • Rahul S. Desikan
  23. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    • Srdjan Djurovic
  24. Vanderbilt Memory & Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Logan Dumitrescu
    •  & Timothy J. Hohman
  25. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA

    • Logan Dumitrescu
    • , Timothy J. Hohman
    •  & Lea K. Davis
  26. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Palmi V. Jonsson
  27. MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK

    • Steven J. Kiddle
  28. Department of Research and Innovation, Helse Fonna, Haugesund, Norway

    • Arvid Rongve
  29. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    • Arvid Rongve
  30. Department of Geriatrics, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway

    • Ingvild Saltvedt
  31. Institute of Health and Society, University of Oslo, Oslo, Norway

    • Geir Selbæk
  32. Department of Neurodegenerative Disorders, Institute of Neurology, UCL, London, UK

    • Maryam Shoai
    •  & John Hardy
  33. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    • Nathan G. Skene
    •  & Jens Hjerling-Leffler
  34. Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK

    • Nathan G. Skene
  35. Department of Psychiatry, Namsos Hospital, Namsos, Norway

    • Eystein Stordal
  36. Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway

    • Eystein Stordal
  37. Memory Clinic, Geriatric Department, Oslo University Hospital, Oslo, Norway

    • Ingun D. Ulstein
  38. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  39. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  40. NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, London, UK

    • Richard Dobson
  41. Institute of Health Informatics Research, University College London, London, UK

    • Richard Dobson
  42. Health Data Research UK London, University College London, London, UK

    • Richard Dobson
  43. Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    • Lea K. Davis
  44. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Stephan Ripke
  45. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Stephan Ripke
  46. Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin, Berlin, Germany

    • Stephan Ripke
  47. Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands

    • Danielle Posthuma

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Contributions

I.E.J. and J.E.S. performed the analyses. D.P. and O.A.A. conceived the idea for the study. D.P. and S.R. supervised analyses. Sv.St. performed quality control on the UK Biobank data and wrote the analysis pipeline. K.W. constructed and applied the FUMA pipeline for performing follow-up analyses. J.B. conducted the single-cell enrichment analyses. J.H.L. and N.S. contributed data. M.S. and J.H. performed polygenic score analyses. D.P. and I.E.J. wrote the first draft of the paper. All other authors contributed data and critically reviewed the paper.

Competing interests

The authors report the following potentially competing financial interests. P.F.S.: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). J.H.L.: Cartana (Scientific Advisor) and Roche (grant recipient). O.A.A.: Lundbeck (speaker’s honorarium). St.St., H.S., and K.S. are employees of deCODE Genetics/Amgen. J.H. is a cograntee of Cytox from Innovate UK (UK Department of Business). D.A. has received research support and/or honoraria from Astra-Zeneca, Lundbeck, Novartis Pharmaceuticals, and GE Health, and serves as a paid consultant for Lundbeck, Eisai, Heptares, and Axovant. All other authors declare no financial interests or potential conflicts of interest.

Corresponding author

Correspondence to Danielle Posthuma.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Note and Supplementary Figures 1–7

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–27

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DOI

https://doi.org/10.1038/s41588-018-0311-9