Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles
Eilis Hannon,
Emma L. Dempster,
Jonathan P. Davies,
Barry Chioza,
Georgina E. T. Blake,
Joe Burrage,
Stefania Policicchio,
Alice Franklin,
Emma M. Walker,
Rosemary A. Bamford,
Leonard C. Schalkwyk,
Jonathan Mill
Affiliations
Eilis Hannon
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Emma L. Dempster
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Jonathan P. Davies
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Barry Chioza
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Georgina E. T. Blake
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Joe Burrage
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Stefania Policicchio
Italian Institute of Technology, Center for Human Technologies (CHT)
Alice Franklin
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Emma M. Walker
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Rosemary A. Bamford
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Leonard C. Schalkwyk
School of Life Sciences, University of Essex
Jonathan Mill
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, RILD Building, Royal Devon & Exeter Hospital
Abstract Background Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. Results We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer’s disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. Conclusions Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.
