Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease
By
Mary Ann A. DeMichele-Sweet,
Lambertus Klei,
Byron Creese,
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 A. Andreassen,
Srdjan Djurovic,
Lavinia Athanasiu,
Davide Seripa,
Barbara Borroni,
Diego Albani,
Gianluigi Forloni,
Patrizia Mecocci,
Alessandro Serretti,
Diana de Ronchi,
Antonis Politis,
Giulia Paroni,
AddNeuroMed Consortium,
Julie Williams,
Richard Mayeux,
Tatiana Foroud,
Agustín Ruiz,
Clive Ballard,
Oscar L. Lopez,
M. Ilyas Kamboh,
Bernie Devlin,
Robert A. 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), affecting ~ 40% to 60% of individuals with AD. AD+P identifies a subgroup of AD patients with poor outcomes. The strongest clinical predictor of AD+P is a greater degree of cognitive impairment than in AD subjects without psychosis (AD-P). Other frequently replicated correlates of AD+P include elevated depressive symptoms. Although the estimated heritability of psychosis in AD is 61%, the underlying genetic sources of this risk are not known. We report a genome-wide meta-analysis of 12,317 AD subjects, with and without psychosis. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in the gene ENPP6 (best SNP 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 (best SNP rs201109606, O.R. 0.65 (0.56-0.76), p=3.24x10-8), had genome-wide significant associations with the risk of psychosis in AD. Psychosis risk in AD demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We had previously observed a negative genetic correlation with schizophrenia, instead we now found a stronger negative correlation with the related phenotype of bipolar disorder. Psychosis risk in AD was not genetically correlated with AD or other neurodegenerative diseases. 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. Study of the genetic mechanisms underlying the associations of loci in ENPP6 and SUMF1 with psychosis in AD are warranted.
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