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http://bura.brunel.ac.uk/handle/2438/27671
Title: | Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease |
Authors: | DeMichele-Sweet, MAA Klei, L Creese, B Harwood, JC Weamer, EA McClain, L Sims, R Hernandez, I Moreno-Grau, S Tárraga, L Boada, M Alarcón-Martín, E Valero, S Liu, Y Hooli, B Aarsland, D Selbaek, G Bergh, S Rongve, A Saltvedt, I Skjellegrind, HK Engdahl, B Stordal, E Andreassen, OA Djurovic, S Athanasiu, L Seripa, D Borroni, B Albani, D Forloni, G Mecocci, P Serretti, A De Ronchi, D Politis, A Williams, J Mayeux, R Foroud, T Ruiz, A Ballard, C Holmans, P Lopez, OL Kamboh, MI Devlin, B Sweet, RA |
Keywords: | diseases;psychiatric disorders |
Issue Date: | 10-Jun-2021 |
Publisher: | Springer Nature |
Citation: | DeMichele-Sweet, M.A.A. et al. (2021) 'Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease', Molecular Psychiatry, 26 (10), pp. 5797 - 5811. 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. |
Description: | 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 online at: https://www.nature.com/articles/s41380-021-01152-8#Sec13 . |
URI: | https://bura.brunel.ac.uk/handle/2438/27671 |
DOI: | https://doi.org/10.1038/s41380-021-01152-8 |
ISSN: | 1359-4184 |
Other Identifiers: | ORCID iD: Mary Ann A. DeMichele-Sweet https://orcid.org/0000-0002-6582-7813 ORCID iD: Byron Creese https://orcid.org/0000-0001-6490-6037 ORCID iD: Rebecca Sims https://orcid.org/0000-0002-3885-1199 ORCID iD: Mercè Boada https://orcid.org/0000-0003-2617-3009 ORCID iD: Yushi Liu https://orcid.org/0000-0003-4185-4187 ORCID iD: Basavaraj Hooli https://orcid.org/0000-0002-5461-1507 ORCID iD: Geir Selbaek https://orcid.org/0000-0001-6511-8219 ORCID iD: Sverre Bergh https://orcid.org/0000-0001-9593-2967 ORCID iD: Arvid Rongve https://orcid.org/0000-0002-0476-4134 ORCID iD: Ingvild Saltvedt https://orcid.org/0000-0002-7897-9808 ORCID iD: Håvard K. Skjellegrind https://orcid.org/0000-0003-3067-0016 ORCID iD: Bo Engdahl https://orcid.org/0000-0002-9166-5782 ORCID iD: Eystein Stordal https://orcid.org/0000-0002-2443-7923 ORCID iD: Ole A. Andreassen https://orcid.org/0000-0002-4461-3568 ORCID iD: Srdjan Djurovic https://orcid.org/0000-0002-8140-8061 ORCID iD: Lavinia Athanasiu https://orcid.org/0000-0002-3321-6997 ORCID iD: Barbara Borroni https://orcid.org/0000-0001-9340-9814 ORCID iD: Diego Albani https://orcid.org/0000-0002-7050-6723 ORCID iD: Alessandro Serretti https://orcid.org/0000-0003-4363-3759 ORCID iD: Antonis Politis https://orcid.org/0000-0003-0261-7517 ORCID iD: Julie Williams https://orcid.org/0000-0002-4069-0259 ORCID iD: Tatiana Foroud https://orcid.org/0000-0002-5549-2212 ORCID iD: Agustin Ruiz https://orcid.org/0000-0003-2633-2495 ORCID iD: Clive Ballard https://orcid.org/0000-0003-0022-5632 ORCID iD: Peter Holmans https://orcid.org/0000-0003-0870-9412 ORCID iD: Oscar L. Lopez https://orcid.org/0000-0002-8546-8256 ORCID iD: Bernie Devlin https://orcid.org/0000-0003-2524-4290 ORCID iD: Robert A. Sweet https://orcid.org/0000-0001-9154-9709 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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FullText.pdf | Copyright © The Author(s), under exclusive licence to Springer Nature Limited 2021. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use (see: https://www.springernature.com/gp/open-research/policies/journal-policies), but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1038/s41380-021-01152-8. | 1.07 MB | Adobe PDF | View/Open |
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