We’re moving! Datasets in the NIAGADS database are being transitioned to the DSS database, more info coming soon.

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

TitleGenome-wide association identifies the first risk loci for psychosis in Alzheimer disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsDeMichele-Sweet, MAnn A, Klei, L, Creese, B, Harwood, JC, Weamer, EA, McClain, L, Sims, R, Hernández, I, Moreno-Grau, S, Tarraga, 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, M Kamboh, I, Devlin, B, Sweet, RA
Corporate AuthorsNIA-LOAD Family Based Study Consortium, Alzheimer’s Disease Genetics Consortium (ADGC)
JournalMol Psychiatry
Date Published2021 Jun 10
ISSN1476-5578
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) 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), 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.

DOI10.1038/s41380-021-01152-8
Alternate JournalMol Psychiatry
PubMed ID34112972
Grant ListAG066468 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
MH057881 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH116046 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
AG030653 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R01 MH116046 / MH / NIMH NIH HHS / United States
AG027224 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /