An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations
Jorge L. Del-Aguila
John P. Budde
Maria Victoria Fernandez
Celeste M. Karch
Randall J. Bateman
John C. Morris
Colin L. Masters
Neill R. Graff-Radford
Jasmeer P. Chhatwal
Samantha Gardener, Edith Cowan UniversityFollow
Ralph Martins, Edith Cowan UniversityFollow
Hamid Sohrabi, Edith Cowan UniversityFollow
Kevin Taddei, Edith Cowan UniversityFollow
Siri Houeland DiBari
Neal Scott Mason
Jee Hoon Roh
Dominantly Inherited Alzheimer Network (DIAN)
School of Medical and Health Sciences
This work was supported by grants from the National Institutes of Health (NIH: grant nos R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777), the Alzheimer Association (grant nos NIRG-11-200110, BAND-14-338165, AARG-16-441560 and BFG-15-362540), grant no. NIH AG046374 (C.M.K.), Tau Consortium (C.M.K.) and grant no. K23 AG049087 (J.P.C.).
The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276.
Data collection and sharing for this project were supported by DIAN (UF1AG032438) funded by the National Institute on Aging, the German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, with partial support by the Research and Development Grants for Dementia from the Japan Agency for Medical Research and Development, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute.
Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA–AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.