Meta-Analysis

. 2021 Oct;26(10):5797-5811.

doi: 10.1038/s41380-021-01152-8. Epub 2021 Jun 10.

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

Mary Ann A DeMichele-Sweet¹, Lambertus Klei¹, Byron Creese^{2

3}, Janet C Harwood⁴, Elise A Weamer⁵, Lora McClain¹, Rebecca Sims⁴, Isabel Hernandez^{6

7}, Sonia Moreno-Grau^{6

7}, Lluís Tárraga^{6

7}, Mercè Boada^{6

7}, Emilio Alarcón-Martín⁶, Sergi Valero^{6

7}; NIA-LOAD Family Based Study Consortium, Alzheimer’s Disease Genetics Consortium (ADGC); Yushi Liu⁸, Basavaraj Hooli⁹, Dag Aarsland¹⁰, Geir Selbaek^{11

12

13}, Sverre Bergh¹⁴, Arvid Rongve¹⁵, Ingvild Saltvedt^{16

17}, Håvard K Skjellegrind^{18

19}, Bo Engdahl²⁰, Eystein Stordal²¹, Ole A Andreassen²², Srdjan Djurovic^{23

24}, Lavinia Athanasiu²⁵, Davide Seripa²⁶, Barbara Borroni²⁷, Diego Albani²⁸, Gianluigi Forloni²⁸, Patrizia Mecocci²⁹, Alessandro Serretti³⁰, Diana De Ronchi³⁰, Antonis Politis³¹, Julie Williams^{4

32}, Richard Mayeux³³, Tatiana Foroud³⁴, Agustin Ruiz^{6

7}, Clive Ballard³⁵, Peter Holmans³⁶, Oscar L Lopez^{1

5}, M Ilyas Kamboh³⁷, Bernie Devlin¹, Robert A Sweet^{38

39}

Affiliations

¹ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
² University of Exeter Medical School, College of Medicine and Health, Exeter, UK.
³ Norwegian, Exeter and King's College Consortium for Genetics of Neuropsychiatric Symptoms in Dementia, Exeter, UK.
⁴ Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
⁵ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.
⁷ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
⁸ Global Statistical Science, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
⁹ Neurodegeneration Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
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.
¹¹ Norwegian National Advisory Unit in Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹² Department Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
¹³ Faculty of Medicine, University of Oslo, Oslo, Norway.
¹⁴ Research Centre of Age-related Functional Decline and Disease, Innlandet Hospital Trust, Pb 68, Ottestad, Norway.
¹⁵ Department of Research and Innovation, Helse Fonna, Haugesund and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.
¹⁶ Geriatric Department, St. Olav Hospital, University Hospital of Trondheim, Trondheim, Norway.
¹⁷ Department of Neuromedicine and Movement science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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.
¹⁹ Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
²⁰ Norwegian Institute of Public Health, Oslo, Norway.
²¹ Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
²² NORMENT Centre, Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway.
²³ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
²⁴ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁵ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²⁶ Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy.
²⁷ Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
²⁸ Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
²⁹ Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
³⁰ Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
³¹ 1st Department of Psychiatry, Eginition Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.
³² UK Dementia Research Institute @ Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
³³ Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA.
³⁴ Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁵ University of Exeter Medical School, Exeter, UK.
³⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
³⁷ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
³⁸ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. sweetra@upmc.edu.
³⁹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. sweetra@upmc.edu.

PMID: 34112972
PMCID: PMC8660923
DOI: 10.1038/s41380-021-01152-8

Meta-Analysis

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

Mary Ann A DeMichele-Sweet et al. Mol Psychiatry. 2021 Oct.

. 2021 Oct;26(10):5797-5811.

doi: 10.1038/s41380-021-01152-8. Epub 2021 Jun 10.

Authors

Affiliations

¹ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
² University of Exeter Medical School, College of Medicine and Health, Exeter, UK.
³ Norwegian, Exeter and King's College Consortium for Genetics of Neuropsychiatric Symptoms in Dementia, Exeter, UK.
⁴ Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
⁵ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.
⁷ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
⁸ Global Statistical Science, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
⁹ Neurodegeneration Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
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.
¹¹ Norwegian National Advisory Unit in Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹² Department Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
¹³ Faculty of Medicine, University of Oslo, Oslo, Norway.
¹⁴ Research Centre of Age-related Functional Decline and Disease, Innlandet Hospital Trust, Pb 68, Ottestad, Norway.
¹⁵ Department of Research and Innovation, Helse Fonna, Haugesund and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.
¹⁶ Geriatric Department, St. Olav Hospital, University Hospital of Trondheim, Trondheim, Norway.
¹⁷ Department of Neuromedicine and Movement science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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.
¹⁹ Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
²⁰ Norwegian Institute of Public Health, Oslo, Norway.
²¹ Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
²² NORMENT Centre, Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway.
²³ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
²⁴ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁵ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²⁶ Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy.
²⁷ Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
²⁸ Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
²⁹ Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
³⁰ Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
³¹ 1st Department of Psychiatry, Eginition Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.
³² UK Dementia Research Institute @ Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
³³ Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA.
³⁴ Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁵ University of Exeter Medical School, Exeter, UK.
³⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
³⁷ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
³⁸ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. sweetra@upmc.edu.
³⁹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. sweetra@upmc.edu.

PMID: 34112972
PMCID: PMC8660923
DOI: 10.1038/s41380-021-01152-8

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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Conflict of interest statement

Conflicts 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.

Figures

**Figure 1.. SNP associations with psychosis in AD.**
**A. Manhattan plot.** The x-axis shows genomic position for autosomes and the X chromosome. The y-axis shows statistical significance as −log10 (P). Each point represents an analyzed SNP. The dashed horizontal line represents the threshold for genome-wide significance (p = 5 × 10⁻⁸). **B–C. Zoom plots of the two genome-wide significant loci.** The x-axis shows genomic position. The left y-axis shows statistical significance as −log10 (P). Each point represents an analyzed SNP, coded by degree of linkage disequilibrium relative to the most significant SNP within the locus. Recombination rate through the region is shown on the right y-axis. AD: Alzheimer Disease; LD: linkage disequilibrium; cM: centimorgans; Mb: megabase

See this image and copyright information in PMC

References

1. Sweet RA, Nimgaonkar VL, Devlin B & Jeste DV Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype. Molecular Psychiatry 8, 383–392 (2003). - PubMed
1. Ropacki SA & Jeste DV Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am. J. Psychiatry 162, 2022–2030 (2005). - PubMed
1. Weamer EA, Emanuel JE, Varon D, Miyahara S, Wilkosz PA, Lopez OL et al. The relationship of excess cognitive impairment in MCI and early Alzheimer’s disease to the subsequent emergence of psychosis. Int. Psychogeriatr 21, 78–85 (2009). - PMC - PubMed
1. Emanuel JE, Lopez OL, Houck PR, Becker JT, Weamer EA, DeMichele-Sweet MA et al. Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. Am. J. Geriatr. Psychiatry 19, 160–168 (2011). - PMC - PubMed
1. Sweet RA, Bennett DA, Graff-Radford NR & Mayeux R Assessment and familial aggregation of psychosis in Alzheimer’s disease from the National Institute on Aging Late Onset Alzheimer’s Disease Family Study. Brain 133, 1155–1162 (2010). - PMC - PubMed

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

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

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Abstract

Conflict of interest statement

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