Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer’s and Parkinson’s diseases

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult...

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Bibliographic Details
Published in:Nature genetics Vol. 52; no. 11; pp. 1158 - 1168
Main Authors: Corces, M. Ryan, Shcherbina, Anna, Kundu, Soumya, Gloudemans, Michael J., Frésard, Laure, Granja, Jeffrey M., Louie, Bryan H., Eulalio, Tiffany, Shams, Shadi, Bagdatli, S. Tansu, Mumbach, Maxwell R., Liu, Boxiang, Montine, Kathleen S., Greenleaf, William J., Kundaje, Anshul, Montgomery, Stephen B., Chang, Howard Y., Montine, Thomas J.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.11.2020
Subjects:
631/208/176
631/208/200
631/208/205/2138
692/699/375/132/1283
692/699/375/365/1718
Adult
Agriculture
Alzheimer Disease - genetics
Animal Genetics and Genomics
Atlases as Topic
Biological Variation, Population
Biomedical and Life Sciences
Biomedicine
Brain - anatomy & histology
Cancer Research
Chromatin Assembly and Disassembly
Cohort Studies
Enhancer Elements, Genetic
Epigenomics
Gene Function
Genetic Heterogeneity
Genetic Predisposition to Disease
Genome-Wide Association Study
Haplotypes
Human Genetics
Humans
Machine Learning
Neurons - physiology
Parkinson Disease - genetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
tau Proteins - genetics
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Description
Summary:Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer’s and Parkinson’s diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson’s disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease. Single-cell chromatin profiling of different brain regions identifies cell-type-specific regulatory elements, and helps to predict functional SNPs for Alzheimer’s and Parkinson’s diseases.
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AUTHOR CONTRIBUTIONS
M.R.C., H.Y.C., and T.J.M. conceived of and designed the project. M.R.C. and T.J.M. compiled the figures and wrote the manuscript with help and input from all authors. A.S. and M.R.C. performed bulk ATAC-seq data processing and analysis. M.R.C. performed all HiChIP data analysis with help from M.R.M. and J.M.G.. J.M.G., M.R.C., and A.S. performed all single-cell ATAC-seq data processing and analysis with supervision from W.J.G., A.K., S.B.M. and H.Y.C.. M.J.G. performed GWAS locus curation, colocalization analysis, and GTEx analysis and M.J.G., L.F., and B.L. performed all LD score regression analysis with supervision from S.B.M.. S.K. and A.S. performed all machine-learning analysis with supervision from A.K.. S.K. and T.E. performed allelic imbalance analyses with supervision from A.K. and S.B.M.. B.H.L., S.S., and M.R.C. performed all ATAC-seq, scATAC-seq, and HiChIP data generation with help from S.T.B. and M.R.M.. K.S.M. curated the frozen tissue specimens used in this work.
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-020-00721-x