Genetic Evidence Supporting a Causal Role of Depression in Alzheimer's Disease

• Type of Material: Article
• Authors: Nadia V Harerimana, Emory University; Yue Liu, Emory University; Ekaterina S Gerasimov, Emory University; Duong Duc, Emory University; Thomas G Beach, Banner Sun Health Research Institute, Sun City, AZ 85351, USA; Eric M Reiman, Arizona State University; Julie A Schneider, Rush University; Patricia Boyle, Rush University; Adriana Lori, Emory University; David A Bennett, Rush University; James Lah, Emory University; Allan Levey, Emory University; Nicholas Seyfried, Emory University; Thomas Wingo, Emory University; Aliza Wingo, Emory University
• Language: English
• Date: 2022-06-13
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2021.11.025
• Title of Journal or Parent Work: BIOLOGICAL PSYCHIATRY
• Volume: 92
• Issue: 1
• Start Page: 25
• End Page: 33
• Keywords: RUSH MEMORY; METAANALYSIS; Life Sciences & Biomedicine; DEMENTIA; SYMPTOMS; Science & Technology; Neurosciences & Neurology; EXPRESSION; RISK-FACTORS; BRAIN; Psychiatry; Neurosciences; MILD COGNITIVE IMPAIRMENT; ASSOCIATION; RAB GTPASES
• Research Categories: Biology, Neuroscience; Chemistry, Biochemistry; Health Sciences, Mental Health; Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Background: Depression has been associated with a higher risk of Alzheimer's disease (AD) in several prospective studies; however, mechanisms underlying this association remain unclear. Methods: We examined genetic correlation between depression and AD using linkage disequilibrium score regression. We then tested for evidence of causality between depression and AD using Mendelian randomization and genome-wide association study results. Subsequently, cis and trans quantitative trait locus analyses for the depression genome-wide association study signals were performed to resolve the genetic signals to specific DNA methylation sites, brain transcripts, and proteins. These transcripts and proteins were then examined for associations with AD and its endophenotypes. Finally, the associations between depression polygenic risk score and AD endophenotypes were examined. Results: We detected a significant genetic correlation between depression and AD, suggesting that they have a shared genetic basis. Furthermore, we found that depression had a causal role in AD through Mendelian randomization but did not find evidence for a causal role of AD on depression. Moreover, we identified 75 brain transcripts and 28 brain proteins regulated by the depression genome-wide association study signals through quantitative trait locus analyses. Of these, 46 transcripts and seven proteins were associated with rates of cognitive decline over time, AD pathologies, and AD diagnosis in two separate cohorts, thus implicating them in AD. In addition, we found that a higher depression polygenic risk score was associated with a faster decline of episodic memory over time. Conclusions: Depression appears to have a causal role in AD, and this causal relationship is likely driven, in part, by the 53 brain transcripts and proteins identified in this study.