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

ABSTRACT: 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.

SUBMITTER: Corces MR

PROVIDER: S-EPMC7606627 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Corces M Ryan MR Shcherbina Anna A Kundu Soumya S Gloudemans Michael J MJ Frésard Laure L Granja Jeffrey M JM Louie Bryan H BH Eulalio Tiffany T Shams Shadi S Bagdatli S Tansu ST Mumbach Maxwell R MR Liu Boxiang B Montine Kathleen S KS Greenleaf William J WJ Kundaje Anshul A Montgomery Stephen B SB Chang Howard Y HY Montine Thomas J TJ

Nature genetics 20201026 11

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 indiv ...[more]

PMID: 33106633

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Project description:BackgroundStriatal dopamine transporter (DAT) binding is a sensitive and specific endophenotype for detecting dopaminergic deficits across Parkinson's disease (PD) spectrum. Molecular and clinical signatures of PD in asymptomatic phases help understand the earliest pathophysiological mechanisms underlying the disease. We aimed to investigate whether blood epigenetic markers are associated with inter-individual variation of striatal DAT binding among healthy elderly individuals. We also investigated whether this potential inter-individual variation can manifest as dysfunction of particular cognitive domains. Omics studies conducted on endophenotypes of PD among healthy asymptomatic individuals can provide invaluable insights into early detection, disease mechanisms, and potential therapeutic targets for PD.MethodWe conducted a blood epigenome-wide association study of striatal DAT binding on 96 healthy individuals using the Illumina EPIC array. For functional annotation of our top results, we employed the enhancer-gene mapping strategy using a midbrain single-nucleus multimodal dataset. Finally, we conducted several investigative regression analyses on several neuropsychological tests across five cognitive domains to assess their association with striatal DAT binding among 250 healthy subjects.ResultsWe identified seven suggestive (P-value<10-5) CpG probes. Specifically, three probes were colocalized with three risk loci previously identified in PD's largest Genome-Wide Association Study (GWAS). UCN5A and APOE loci were identified as suggestive DMRs associated with striatal DAT binding. Functional analyses prioritized the FDFT1 gene as the potential target gene in the previously reported CTSB GWAS locus. We also showed that delayed recall memory impairment was correlated with reduced striatal DAT binding, irrespective of age.ConclusionOur study suggested epigenetic and cognitive signatures of striatal DAT binding among healthy individuals, providing valuable insights for future experimental and clinical studies of early PD.

Project description:Recent genome-wide association studies have identified 78 loci associated with Parkinson's disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson's-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson's disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson's disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson's disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson's and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson's therapeutics.

Dataset Information

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

Publications

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

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