Nadia V Harerimana1, Yue Liu1, Ekaterina S Gerasimov1, Duc Duong2, Thomas G Beach3, Eric M Reiman4, Julie A Schneider5, Patricia Boyle5, Adriana Lori6, David A Bennett5, James J Lah1, Allan I Levey1, Nicholas T Seyfried2, Thomas S Wingo7, Aliza P Wingo8. 1. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia. 2. Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia. 3. Banner Sun Health Research Institute, Sun City, Arizona. 4. Banner Alzheimer's Institute, Arizona State University and University of Arizona, Phoenix, Arizona. 5. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois. 6. Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia. 7. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia. Electronic address: thomas.wingo@emory.edu. 8. Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia; Division of Mental Health, Atlanta VA Medical Center, Decatur, Georgia. Electronic address: aliza.wingo@emory.edu.
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. Published by Elsevier Inc.
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. Published by Elsevier Inc.
Authors: Brendan K Bulik-Sullivan; Po-Ru Loh; Hilary K Finucane; Stephan Ripke; Jian Yang; Nick Patterson; Mark J Daly; Alkes L Price; Benjamin M Neale Journal: Nat Genet Date: 2015-02-02 Impact factor: 38.330
Authors: David A Bennett; Julie A Schneider; Aron S Buchman; Lisa L Barnes; Patricia A Boyle; Robert S Wilson Journal: Curr Alzheimer Res Date: 2012-07 Impact factor: 3.498
Authors: Stephen D Ginsberg; Elliott J Mufson; Melissa J Alldred; Scott E Counts; Joanne Wuu; Ralph A Nixon; Shaoli Che Journal: J Chem Neuroanat Date: 2011-06-12 Impact factor: 3.052
Authors: Aliza P Wingo; Yue Liu; Ekaterina S Gerasimov; Jake Gockley; Benjamin A Logsdon; Duc M Duong; Eric B Dammer; Chloe Robins; Thomas G Beach; Eric M Reiman; Michael P Epstein; Philip L De Jager; James J Lah; David A Bennett; Nicholas T Seyfried; Allan I Levey; Thomas S Wingo Journal: Nat Genet Date: 2021-01-28 Impact factor: 38.330
Authors: David M Howard; Mark J Adams; Toni-Kim Clarke; Jonathan D Hafferty; Jude Gibson; Masoud Shirali; Jonathan R I Coleman; Saskia P Hagenaars; Joey Ward; Eleanor M Wigmore; Clara Alloza; Xueyi Shen; Miruna C Barbu; Eileen Y Xu; Heather C Whalley; Riccardo E Marioni; David J Porteous; Gail Davies; Ian J Deary; Gibran Hemani; Klaus Berger; Henning Teismann; Rajesh Rawal; Volker Arolt; Bernhard T Baune; Udo Dannlowski; Katharina Domschke; Chao Tian; David A Hinds; Maciej Trzaskowski; Enda M Byrne; Stephan Ripke; Daniel J Smith; Patrick F Sullivan; Naomi R Wray; Gerome Breen; Cathryn M Lewis; Andrew M McIntosh Journal: Nat Neurosci Date: 2019-02-04 Impact factor: 28.771
Authors: Zhihong Zhu; Zhili Zheng; Futao Zhang; Yang Wu; Maciej Trzaskowski; Robert Maier; Matthew R Robinson; John J McGrath; Peter M Visscher; Naomi R Wray; Jian Yang Journal: Nat Commun Date: 2018-01-15 Impact factor: 14.919
Authors: Anke Hüls; Chloe Robins; Karen N Conneely; Philip L De Jager; David A Bennett; Michael P Epstein; Thomas S Wingo; Aliza P Wingo Journal: Transl Psychiatry Date: 2020-07-30 Impact factor: 6.222