Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
By
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,
Mèrce Boada,
Emilio Alarcón-Martin,
Sergi Valero,
NIA-LOAD Family Based Study Consortium,
Alzheimers Disease Genetics Consortium ADGC,
Yushi Liu,
Basavaraj Hooli,
Dag Aarsland,
Geir Selbaek,
Sverre Bergh,
Arvid Rongve,
Ingvild Saltvedt,
Håvard Skjellegrind,
Bo Engdahl,
Eystein Stordal,
Ole Andreassen,
Srdjan Djurovic,
Lavinia Athanasiu,
Davide Seripa,
Barbara Borroni,
Diego Albani,
Gianluigi Forloni,
Patrizia Mecocci,
Alessandro Serretti,
Diana de Ronchi,
Antonis Politis,
AddNeuroMed Consortium,
Julie Williams,
Richard Mayeux,
Tatiana Foroud,
Agustín Ruiz,
Clive Ballard,
Peter Holmans,
Oscar L. Lopez,
M. Ilyas Kamboh,
Bernie Devlin,
Robert Sweet
Posted 11 Aug 2020
medRxiv DOI: 10.1101/2020.08.07.20139261
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=1.26x10-8) and one spanning the 3-prime-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24x10-8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype epsilon-4. 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 epsilon-4. 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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