A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

AbstractA major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

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Can cancer GWAS variants modulate immune cells in the tumor microenvironment?

10.1101/493171 ◽

2018 ◽

Author(s):

Yi Zhang ◽

Mohith Manjunath ◽

Jialu Yan ◽

Brittany A. Baur ◽

Shilu Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Immune Cells ◽

Cancer Susceptibility ◽

Association Studies ◽

Immune Surveillance ◽

Tumor Infiltrating Lymphocytes ◽

Cell Types ◽

Potential Effect ◽

Chromatin Interaction ◽

Genome Wide Association Studies

AbstractGenome-wide association studies (GWAS) have hitherto identified several genetic variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized. Recent studies have begun to uncover the regulatory potential of non-coding GWAS SNPs by using epigenetic information in corresponding cancer cell types and matched normal tissues. However, this approach does not explore the potential effect of risk germline variants on other important cell types that constitute the microenvironment of tumor or its precursor. This paper presents evidence that the breast cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor infiltrating lymphocytes. CTSW is a candidate tumor-suppressor gene, with expression highly specific to immune cells and also positively correlated with breast cancer patient survival. Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3’ end of CTSW through three-dimensional chromatin interaction. Our work thus poses the possibility that a cancer-associated genetic variant might regulate a gene not only in the cell of cancer origin, but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.

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Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration

Nature Communications ◽

10.1038/s41467-019-12780-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 32

Author(s):

Madhvi Menon ◽

Shahin Mohammadi ◽

Jose Davila-Velderrain ◽

Brittany A. Goods ◽

Tanina D. Cadwell ◽

...

Keyword(s):

Macular Degeneration ◽

Single Cell ◽

Association Studies ◽

Enrichment Analysis ◽

Cell Types ◽

Age Related Macular Degeneration ◽

Retinal Cell ◽

Genome Wide Association Studies ◽

Human Retina ◽

Age Related

Abstract Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. Using a multi-resolution network-based analysis, we identify all major retinal cell types, and their corresponding gene expression signatures. Heterogeneity is observed within macroglia, suggesting that human retinal glia are more diverse than previously thought. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. These data provide a detailed analysis of the human retina, and show how scRNA-seq can provide insight into cell types involved in complex, inflammatory genetic diseases.

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A large-scale genome-wide enrichment analysis identifies new trait-associated genes, pathways and tissues across 31 human phenotypes*

10.1101/160770 ◽

2017 ◽

Cited By ~ 5

Author(s):

Xiang Zhu ◽

Matthew Stephens

Keyword(s):

Complex Traits ◽

Large Scale ◽

Late Onset ◽

Association Studies ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Enrichment Analysis ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Artery Disease

Genome-wide association studies (GWAS) aim to identify genetic factors that are associated with complex traits. Standard analyses test individual genetic variants, one at a time, for association with a trait. However, variant-level associations are hard to identify (because of small effects) and can be difficult to interpret biologically. “Enrichment analyses” help address both these problems by focusing on sets of biologically-related variants. Here we introduce a new model-based enrichment analysis method that requires only GWAS summary statistics, and has several advantages over existing methods. Applying this method to interrogate 3,913 biological pathways and 113 tissue-based gene sets in 31 human phenotypes identifies many previously-unreported enrichments. These include enrichments of the endochondral ossification pathway for adult height, the NFAT-dependent transcription pathway for rheumatoid arthritis, brain-related genes for coronary artery disease, and liver-related genes for late-onset Alzheimer’s disease. A key feature of our method is that inferred enrichments automatically help identify new trait-associated genes. For example, accounting for enrichment in lipid transport genes yields strong evidence for association between MTTP and low-density lipoprotein levels, whereas conventional analyses of the same data found no significant variants near this gene.

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Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

10.1101/655670 ◽

2019 ◽

Cited By ~ 9

Author(s):

Ana Viñuela ◽

Arushi Varshney ◽

Martijn van de Bunt ◽

Rashmi B. Prasad ◽

Olof Asplund ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Variants ◽

Complex Traits ◽

Large Scale ◽

Association Studies ◽

Cell Types ◽

Genome Wide Association Studies ◽

Selective Enrichment ◽

Gwas Signal

AbstractMost signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

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Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

Science Advances ◽

10.1126/sciadv.abc8696 ◽

2020 ◽

Vol 6 (49) ◽

pp. eabc8696

Author(s):

Noboru J. Sakabe ◽

Ivy Aneas ◽

Nicholas Knoblauch ◽

Debora R. Sobreira ◽

Nicole Clark ◽

...

Keyword(s):

Preterm Birth ◽

Stromal Cells ◽

Target Genes ◽

Association Studies ◽

Cell Types ◽

Chromatin Interaction ◽

Open Chromatin ◽

Genome Wide Association Studies ◽

Functional Annotations ◽

Gestational Duration

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

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