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Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease

Molecular Psychiatry volume 26, pages 5797–5811 (2021)Cite this article

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Abstract

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD − P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10−8) and one spanning the 3′-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56–0.76), p = 3.24 × 10−8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

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Fig. 1: SNP associations with psychosis in AD.

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Acknowledgements

This study was supported by the following federal grants: AG027224 (RAS), MH116046 (RAS), MH057881 (BD), AG030653 (MIK), AG041718 (MIK), AG066468 (OLL). Authors in the NIA-LOAD Family Based Study Consortium are Tatiana Foroud, M. Ilyas Kamboh, Oscar L. Lopez, and Richard Mayeux. Authors in the Alzheimer’s Disease Genetics Consortium (ADGC) are Tatiana Foroud, Richard Mayeux, and Robert A. Sweet. A complete list of contributing individuals, consortia, and their grant support can be found in Supplementary Acknowledgements.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Mary Ann A. DeMichele-Sweet, Lambertus Klei, Lora McClain, Oscar L. Lopez, Bernie Devlin & Robert A. Sweet

  2. University of Exeter Medical School, College of Medicine and Health, Exeter, UK

    Byron Creese

  3. Norwegian, Exeter and King’s College Consortium for Genetics of Neuropsychiatric Symptoms in Dementia, Exeter, UK

    Byron Creese

  4. Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK

    Janet C. Harwood, Rebecca Sims & Julie Williams

  5. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Elise A. Weamer, Oscar L. Lopez & Robert A. Sweet

  6. Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain

    Isabel Hernandez, Sonia Moreno-Grau, Lluís Tárraga, Mercè Boada, Emilio Alarcón-Martín, Sergi Valero & Agustin Ruiz

  7. CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain

    Isabel Hernandez, Sonia Moreno-Grau, Lluís Tárraga, Mercè Boada, Sergi Valero & Agustin Ruiz

  8. Global Statistical Science, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

    Yushi Liu

  9. Neurodegeneration Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

    Basavaraj Hooli

  10. Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London and Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway

    Dag Aarsland

  11. Norwegian National Advisory Unit in Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway

    Geir Selbaek

  12. Department Geriatric Medicine, Oslo University Hospital, Oslo, Norway

    Geir Selbaek

  13. Faculty of Medicine, University of Oslo, Oslo, Norway

    Geir Selbaek

  14. Research Centre of Age-related Functional Decline and Disease, Innlandet Hospital Trust, Pb 68, Ottestad, Norway

    Sverre Bergh

  15. Department of Research and Innovation, Helse Fonna, Haugesund and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway

    Arvid Rongve

  16. Geriatric Department, St. Olav Hospital, University Hospital of Trondheim, Trondheim, Norway

    Ingvild Saltvedt

  17. Department of Neuromedicine and Movement science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    Ingvild Saltvedt

  18. HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Levanger, Norway

    Håvard K. Skjellegrind

  19. Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway

    Håvard K. Skjellegrind

  20. Norwegian Institute of Public Health, Oslo, Norway

    Bo Engdahl

  21. Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway

    Eystein Stordal

  22. NORMENT Centre, Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway

    Ole A. Andreassen

  23. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Srdjan Djurovic

  24. NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway

    Srdjan Djurovic

  25. NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Lavinia Athanasiu

  26. Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy

    Davide Seripa

  27. Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

    Barbara Borroni

  28. Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

    Diego Albani & Gianluigi Forloni

  29. Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy

    Patrizia Mecocci

  30. Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy

    Alessandro Serretti & Diana De Ronchi

  31. 1st Department of Psychiatry, Eginition Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece

    Antonis Politis

  32. UK Dementia Research Institute @ Cardiff, School of Medicine, Cardiff University, Cardiff, UK

    Julie Williams

  33. Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA

    Richard Mayeux

  34. Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Tatiana Foroud

  35. University of Exeter Medical School, Exeter, UK

    Clive Ballard

  36. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK

    Peter Holmans

  37. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    M. Ilyas Kamboh

Authors
  1. Mary Ann A. DeMichele-Sweet
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  2. Lambertus Klei
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  3. Byron Creese
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  4. Janet C. Harwood
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  5. Elise A. Weamer
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  6. Lora McClain
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  7. Rebecca Sims
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  8. Isabel Hernandez
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  9. Sonia Moreno-Grau
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  10. Lluís Tárraga
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  11. Mercè Boada
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  12. Emilio Alarcón-Martín
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  13. Sergi Valero
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  14. Yushi Liu
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  15. Basavaraj Hooli
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  16. Dag Aarsland
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  17. Geir Selbaek
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  18. Sverre Bergh
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  19. Arvid Rongve
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  21. Håvard K. Skjellegrind
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  29. Diego Albani
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  32. Alessandro Serretti
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  33. Diana De Ronchi
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  34. Antonis Politis
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  35. Julie Williams
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  36. Richard Mayeux
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  37. Tatiana Foroud
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  39. Clive Ballard
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  40. Peter Holmans
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  41. Oscar L. Lopez
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  42. M. Ilyas Kamboh
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  43. Bernie Devlin
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  44. Robert A. Sweet
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Consortia

NIA-LOAD Family Based Study Consortium, Alzheimer’s Disease Genetics Consortium (ADGC)

Contributions

Each author is expected to have made substantial contributions: (1) to the conception or design of the work; RAS, BD, MIK, CB, OLL. (2) to the acquisition, analysis, or interpretation of data; MAAD-S, LK, BC, JCH, EAW, LM, RS, IH, SM-G, LT, MB, EA-M, SV, YL, BH, DA, GS, SB, AR, IS, HKS, BE, ES, OAA, SD, LA, DS, BB, DA, GF, PM, AS, DDR, AP, JW, RM, TF, AR, CB, PH, OLL, MIK, BD, RAS. (3) to the creation of new software used in the work; YL. (4) have drafted the manuscript or substantively revised it. MAAD-S, JCH, LK, BC, LM, CB, PH, MIK, BD, RAS. Each author has approved the submitted version (and any substantially modified version that involves the author’s contribution to the study) and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Corresponding author

Correspondence to Robert A. Sweet.

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Conflict of interest

YL and BH are currently employed by and holding stock in Eli Lilly and Company. CB reports grants and personal fees from Acadia pharmaceutical company, grants and personal fees from Lundbeck, personal fees from Roche, personal fees from Otsuka, personal fees from Biogen, personal fees from Eli Lilly, personal fees from Novo Nordisk, personal fees from AARP, grants and personal fees from Synexus, personal fees from Exciva, outside the submitted work. OLL served as a consultant for Grifols, Inc. IS has been investigator in the drug trial Boehringer‐Ingelheim 1346.0023. OAA is a consultant to HEALTHLYTIX, speaker honoraria from Lundbeck. AS is or has been a consultant to or has received honoraria or grants unrelated to the present work from: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. MB is a consultant to GRIFOLS, BIOGEN, ROCHE, LILLY, CORTEXYME, ARACLON, MERCK. Grants La Caixa, IMI, ISCIII. DS reports personal fees from Biogen.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Members of the NIA-LOAD Family Based Study Consortium and Alzheimer’s Disease Genetics Consortium (ADGC) are listed in Supplementary information.

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DeMichele-Sweet, M.A.A., Klei, L., Creese, B. et al. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry 26, 5797–5811 (2021). https://doi.org/10.1038/s41380-021-01152-8

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