Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease - Nasjonal kompetansetjeneste for aldring og helse

Molecular Psychiatry, 2021

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

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.


Mary Ann A. DeMichele-Sweet, Lambertus Klei, Byron Creese, Janet C. Harwood, Elise A. Weamer, Lora McClain, Rebecca Sims, Isabel Hernandez, Sonia Moreno-Grau, Lluís Tárraga, Mercè Boada, Emilio Alarcón-Martín, Sergi Valero, NIA-LOAD Family Based Study Consortium, Alzheimer’s Disease Genetics Consortium (ADGC), Yushi Liu, Basavaraj Hooli, Dag Aarsland, Geir Selbaek, Sverre Bergh, Arvid Rongve, Ingvild Saltvedt, Håvard K. Skjellegrind, Bo Engdahl, Eystein Stordal, Ole A. Andreassen, Srdjan Djurovic, Lavinia Athanasiu, Davide Seripa, Barbara Borroni, Diego Albani, Gianluigi Forloni, Patrizia Mecocci, Alessandro Serretti, Diana De Ronchi, Antonis Politis, Julie Williams, Richard Mayeux, Tatiana Foroud, Agustin Ruiz, Clive Ballard, Peter Holmans, Oscar L. Lopez, M. Ilyas Kamboh, Bernie Devlin & Robert A. Sweet