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author DeMichele-Sweet, Mary Ann A.
Klei, Lambertus
Creese, Byron
Harwood, Janet C.
Weamer, Elise A.
McClain, Lora
Sims, Rebecca
Hernandez, Isabel
Moreno-Grau, Sonia
Tárraga, Lluís
Boada, Mercè
Alarcón-Martín, Emilio
Valero, Sergi
Liu, Yushi
Hooli, Basavaraj
Aarsland, Dag
Selbaek, Geir
Bergh, Sverre
Rongve, Arvid
Saltvedt, Ingvild
Skjellegrind, Håvard K.
Engdahl, Bo
Stordal, Eystein
Andreassen, Ole A.
Djurovic, Srdjan
Athanasiu, Lavinia
Seripa, Davide
Borroni, Barbara
Albani, Diego
Forloni, Gianluigi
Mecocci, Patrizia
Serretti, Alessandro
De Ronchi, Diana
Politis, Antonis
Williams, Julie
Mayeux, Richard
Foroud, Tatiana
Ruiz, Agustín
Ballard, Clive
Holmans, Peter
Lopez, Oscar L.
Kamboh, M. Ilyas
Devlin, Bernie
Sweet, Robert A.
author_facet DeMichele-Sweet, Mary Ann A.
Klei, Lambertus
Creese, Byron
Harwood, Janet C.
Weamer, Elise A.
McClain, Lora
Sims, Rebecca
Hernandez, Isabel
Moreno-Grau, Sonia
Tárraga, Lluís
Boada, Mercè
Alarcón-Martín, Emilio
Valero, Sergi
Liu, Yushi
Hooli, Basavaraj
Aarsland, Dag
Selbaek, Geir
Bergh, Sverre
Rongve, Arvid
Saltvedt, Ingvild
Skjellegrind, Håvard K.
Engdahl, Bo
Stordal, Eystein
Andreassen, Ole A.
Djurovic, Srdjan
Athanasiu, Lavinia
Seripa, Davide
Borroni, Barbara
Albani, Diego
Forloni, Gianluigi
Mecocci, Patrizia
Serretti, Alessandro
De Ronchi, Diana
Politis, Antonis
Williams, Julie
Mayeux, Richard
Foroud, Tatiana
Ruiz, Agustín
Ballard, Clive
Holmans, Peter
Lopez, Oscar L.
Kamboh, M. Ilyas
Devlin, Bernie
Sweet, Robert A.
author_sort DeMichele-Sweet, Mary Ann A.
collection PubMed
description 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, 5,445 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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spelling pubmed-86609232022-01-15 Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease DeMichele-Sweet, Mary Ann A. Klei, Lambertus Creese, Byron Harwood, Janet C. Weamer, Elise A. McClain, Lora Sims, Rebecca Hernandez, Isabel Moreno-Grau, Sonia Tárraga, Lluís Boada, Mercè Alarcón-Martín, Emilio Valero, Sergi Liu, Yushi Hooli, Basavaraj Aarsland, Dag Selbaek, Geir Bergh, Sverre Rongve, Arvid Saltvedt, Ingvild Skjellegrind, Håvard K. Engdahl, Bo Stordal, Eystein Andreassen, Ole A. Djurovic, Srdjan Athanasiu, Lavinia Seripa, Davide Borroni, Barbara Albani, Diego Forloni, Gianluigi Mecocci, Patrizia Serretti, Alessandro De Ronchi, Diana Politis, Antonis Williams, Julie Mayeux, Richard Foroud, Tatiana Ruiz, Agustín Ballard, Clive Holmans, Peter Lopez, Oscar L. Kamboh, M. Ilyas Devlin, Bernie Sweet, Robert A. Mol Psychiatry Article 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, 5,445 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. 2021-10 2021-06-10 /pmc/articles/PMC8660923/ /pubmed/34112972 http://dx.doi.org/10.1038/s41380-021-01152-8 Text en <p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: <uri xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></p>
spellingShingle Article
DeMichele-Sweet, Mary Ann A.
Klei, Lambertus
Creese, Byron
Harwood, Janet C.
Weamer, Elise A.
McClain, Lora
Sims, Rebecca
Hernandez, Isabel
Moreno-Grau, Sonia
Tárraga, Lluís
Boada, Mercè
Alarcón-Martín, Emilio
Valero, Sergi
Liu, Yushi
Hooli, Basavaraj
Aarsland, Dag
Selbaek, Geir
Bergh, Sverre
Rongve, Arvid
Saltvedt, Ingvild
Skjellegrind, Håvard K.
Engdahl, Bo
Stordal, Eystein
Andreassen, Ole A.
Djurovic, Srdjan
Athanasiu, Lavinia
Seripa, Davide
Borroni, Barbara
Albani, Diego
Forloni, Gianluigi
Mecocci, Patrizia
Serretti, Alessandro
De Ronchi, Diana
Politis, Antonis
Williams, Julie
Mayeux, Richard
Foroud, Tatiana
Ruiz, Agustín
Ballard, Clive
Holmans, Peter
Lopez, Oscar L.
Kamboh, M. Ilyas
Devlin, Bernie
Sweet, Robert A.
Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
title Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
title_full Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
title_fullStr Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
title_full_unstemmed Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
title_short Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
title_sort genome-wide association identifies the first risk loci for psychosis in alzheimer disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660923/
https://www.ncbi.nlm.nih.gov/pubmed/34112972
http://dx.doi.org/10.1038/s41380-021-01152-8
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