Abstract
Alzheimer’s disease (AD) is a multifactorial disease that affects more than 5 million Americans. Multiple pathways might be involved in the AD pathogenesis. The implication of lipid genetic susceptibility on brain gene expression is yet to be investigated. The current study included 192 brain samples from AD patients who were enrolled in the ROSMAP study. The samples were genotyped and imputed to the HRC Reference Panel. Lipid polygenetic risk score was constructed from the weighted sum of genetic variants associated with low-density lipoprotein cholesterol (LDL-C). The gene expression was profiled by RNA sequencing, and the association of gene expression with lipid polygenetic risk scores was tested by linear regression models adjusted for age, sex and APOE e4 alleles. Three genes were found to associate with lipid polygenetic risk scores, including HMCN2 (P = 3.6 × 10–7), PDLIM5 (P = 1.2 × 10–6), and FHL5 (P = 2.0 × 10–6). Network analysis revealed multiple related pathways, including dopaminergic synapse (P = 4.5 × 10–5), circadian entrainment (P = 1.1 × 10–4), and cholinergic synapse (P = 2.3 × 10–4). Our study underscores the importance of lipid regulation and metabolism to AD heterogeneity.
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Acknowledgements
This project was supported by Boston University Digital Health Initiative and the Alzheimer’s Association Grant (AARG-NTF-20-643020). The results published here are in part based on data obtained from the AMP-AD Knowledge Portal (https://doi.org/10.7303/syn2580853). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, U01AG61356, the Illinois Department of Public Health, and the Translational Genomics Research Institute. We thank the patients and their families for their selfless donation to further understanding Alzheimer’s disease. More information on how to access Religious Orders Study and Rush Memory and Aging Project data can be found at www.radc.rush.edu and www.synapse.org. This project was supported by funding from the National Institute on Aging (AG034504 and AG041232). Many data and biomaterials were collected from several National Institute on Aging (NIA) and National Alzheimer’s Coordinating Center (NACC, Grant #U01 AG016976) funded sites. Amanda J. Myers, PhD (University of Miami, Department of Psychiatry) prepared the series. Quality control checks and preparation of the gene expression data were provided by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania.
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XM and HL initiated the study and drafted the manuscript. WL, BF and HL performed the analyses. All authors critically reviewed the manuscript and approved the final version of the manuscript.
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Miao, X., Liu, W., Fan, B. et al. Transcriptomic Heterogeneity of Alzheimer’s Disease Associated with Lipid Genetic Risk. Neuromol Med 22, 534–541 (2020). https://doi.org/10.1007/s12017-020-08610-6
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DOI: https://doi.org/10.1007/s12017-020-08610-6