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

Abstract

Genome-wide association studies (GWAS) of neurological diseases have identified thousands of variants associated with disease phenotypes. However, the majority 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 (3D) 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 single-nucleotide polymorphisms (SNPs) for Alzheimer’s disease (AD) and Parkinson’s disease (PD), nominating target genes and cell types for previously orphaned GWAS loci. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands our understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes

“…Importantly, human sequence variants affecting complex traits and diseases are enriched in non-coding sequences ( Maurano et al, 2015 ; Pickrell, 2014 ). Thus, cell-type-specific profiles derived from single-cell chromatin accessibility data can help prioritize the cell types of action and function of these variants ( Chiou et al, 2019 ; Corces et al, 2020 ).…”

A cell atlas of chromatin accessibility across 25 adult human tissues

“…We further incorporated this dataset alongside single cell chromatin accessibility data from human fetal tissues (Domcke et al, 2020), to reveal the regulatory elements that may govern life stage-specific cellular roles. The atlas of chromatin accessibility reported here is thus highly complementary to emerging atlases of chromatin accessibility in human fetal tissues (Domcke et al, 2020) and in individual human organ systems (Chiou et al, 2019;Corces et al, 2020;Hocker et al, 2020;. Integration of these datasets along with future human single cell datasets of increasing scale, breadth, and depth will enable a comprehensive understanding of gene regulatory features of human cell types throughout the lifespan.…”

“…Genetic variants associated with complex diseases and traits from GWAS predominantly reside in non-coding regions of the genome (Claussnitzer et al, 2020) and are enriched in cCREs in a tissue and cell type-specific fashion (Corces et al, 2020;Cusanovich et al, 2018;Domcke et al, 2020;Hocker et al, 2020;Maurano et al, 2012;Song et al, 2020;Song et al, 2019). To examine the genome-wide enrichment of disease and trait associated variants within cCREs annotated in each of the 54 human cell types characterized in the current study, we performed cell typestratified linkage disequilibrium score regression (LDSC) analysis using GWAS summary statistics for 56 phenotypes including diseases and non-disease traits ( Figure 6A-B, Table S9, See Methods).…”

“…The resulting data can be used to deconvolute cell types from mixed cell populations and to dissect cell type-specific transcriptomic and epigenomic states in primary tissues. While these tools have been applied to mammalian tissues including murine biosamples (Cusanovich et al, 2018;Lareau et al, 2019;Li et al, 2020;Preissl et al, 2018;Sinnamon et al, 2019), human fetal tissues (Domcke et al, 2020), and individual adult human organ systems (Chiou et al, 2019;Corces et al, 2020;Hocker et al, 2020;, we still lack comprehensive maps of cCREs in the cell types comprising primary tissues of the adult human body.…”

Applying Artificial Intelligence to Multi‐Omic Data: New Functional Variants in Parkinson's Disease

“…Therefore, their significance has been debated since it is difficult to establish the causal variant. To address this gap, Corces et al 1 used an integrative, multi‐omic approach to uncover the functions of non‐coding PD GWAS variants.…”