Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms of Autoimmune Disease
Open accessPublished version of a preprint
Abstract
Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The vast majority of genome-wide association study loci encode genes obviously active in the immune system, and particularly in the lymphocyte lineage, placing beyond a doubt the nature of multiple sclerosis as autoimmune.
“The vast majority of GWAS loci encode genes obviously active in the immune system,45, 63 and particularly in the lymphocyte lineage,64 placing beyond a doubt the nature of the disease as autoimmune.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [64]
Significant enrichment of risk alleles on open chromatin elements was detected in 25/48 multiple sclerosis risk loci, due to 177 DNase I hypersensitive sites out of a total of more than 500,000 DHS sites present in all 48 loci.
“We were able to detect significant enrichment of risk alleles on open chromatin elements in 25/48 MS risk loci and that these were due to 177 DHS, of a total of > 500 000 DHS sites present in all 48 loci.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [64]
Correlating the pattern of accessibility of each of the 177 DNase I hypersensitive sites to gene expression across REMC 56 tissues identified 49 genes in 17/25 loci that show clear evidence of regulation by risk-burdened DHS sites.
“We then correlated the pattern of accessibility of each of these 177 DHS sites to gene expression across REMC 56 tissues and identified 49 genes in 17/25 loci that show clear evidence of regulation by risk‐burdened DHS sites.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [64]
The DNase I hypersensitive sites are preferentially accessible in immune cell subsets, particularly T cells and their precursors, and the 49 genes are strongly expressed in these tissues.
“As expected, the DHS are preferentially accessible in immune cell subsets, particularly T cells and their precursors, and the 49 genes are strongly expressed in these tissues.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [64]
A specific DHS site drives risk to MS, type 1 diabetes and autoimmune thyroiditis in the MND1 locus.
“a specific DHS site driving risk to MS, type 1 diabetes and autoimmune thyroiditis in the MND1 locus64”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [64]
Cites
Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes
Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S., & Goldstein, D. B. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003709 · Cited by 901 · see citing works
The International IBD Genetics Consortium (IIBDGC), Ellinghaus, D., International Genetics of Ankylosing Spondylitis Consortium (IGAS), International PSC Study Group (IPSCSG), Genetic Analysis of Psoriasis Consortium (GAPC), Psoriasis Association Genetics Extension (PAGE), Jostins, L., Spain, S. L., Cortes, A., Bethune, J., et al. (2016) · Nature Genetics · doi:10.1038/ng.3528 · Cited by 751 · see citing works
Fine-mapping inflammatory bowel disease loci to single-variant resolution
International Inflammatory Bowel Disease Genetics Consortium, Huang, H., Fang, M., Jostins, L., Umićević Mirkov, M., Boucher, G., Anderson, C. A., Andersen, V., Cleynen, I., Cortes, A., et al. (2017) · Nature · doi:10.1038/nature22969 · Cited by 611 · see citing works
Self-citationPartitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
Gusev, A., Lee, S. H., Trynka, G., Finucane, H., Vilhjálmsson, B. J., Xu, H., Zang, C., Ripke, S., Bulik-Sullivan, B., Stahl, E., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.10.004 · Cited by 544 · see citing works
Self-citationPromise and pitfalls of the Immunochip
Cortes, A., & Brown, M. A. (2010) · Arthritis Research & Therapy · doi:10.1186/ar3204 · Cited by 479 · see citing works
Corradin, O., Saiakhova, A., Akhtar-Zaidi, B., Myeroff, L., Willis, J., Cowper-Sal·lari, R., Lupien, M., Markowitz, S., & Scacheri, P. C. (2014) · Genome Research · doi:10.1101/gr.164079.113 · Cited by 366 · see citing works
Cordell, H. J., Han, Y., Mells, G. F., Li, Y., Hirschfield, G. M., Greene, C. S., Xie, G., Juran, B. D., Zhu, D., Qian, D. C., et al. (2015) · Nature Communications · doi:10.1038/ncomms9019 · Cited by 287 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
International Multiple Sclerosis Genetics Consortium, Patsopoulos, N. A., Baranzini, S. E., Santaniello, A., Shoostari, P., Cotsapas, C., Wong, G., Beecham, A. H., James, T., Replogle, J., et al. (2019) · Science · doi:10.1126/science.aav7188 · Cited by 1,471 · see citing works
Self-citationDe novo mutations in regulatory elements in neurodevelopmental disorders
Short, P. J., McRae, J. F., Gallone, G., Sifrim, A., Won, H., Geschwind, D. H., Wright, C. F., Firth, H. V., FitzPatrick, D. R., Barrett, J. C., et al. (2018) · Nature · doi:10.1038/nature25983 · Cited by 274 · see citing works
Extreme Polygenicity of Complex Traits Is Explained by Negative Selection
O'Connor, L. J., Schoech, A. P., Hormozdiari, F., Gazal, S., Patterson, N., & Price, A. L. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.07.003 · Cited by 268 · see citing works
Genome‐wide association studies of multiple sclerosis
Cotsapas, C., & Mitrovic, M. (2018) · Clinical & Translational Immunology · doi:10.1002/cti2.1018 · Cited by 89 · see citing works
Self-citation
- Authors
- Shooshtari, P., Huang, H., & Cotsapas, C.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Cotsapas, Chris
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 101
- Issue
- 1
- Pages
- 75-86
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5501874
- OpenAlex
- W2727796273
- Cited by
- 33
- References
- 7
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 8 · 2018: 7 · 2017: 1 · 2016: 1
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biogen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- autoimmune disease, inflammatory diseases, disease risk loci, DNase I hypersensitive sites, regulatory elements, epigenetics, gene expression regulation, non-coding DNA
- MeSH terms
- Alleles, Autoimmune Diseases, Chromosomes, Human, Pair 6, Deoxyribonuclease I, Humans, Inflammation, Organ Specificity, Regulatory Sequences, Nucleic Acid, Risk Factors, Reproducibility of Results, Genetic Predisposition to Disease, Physical Chromosome Mapping, Epigenesis, Genetic, Genome-Wide Association Study, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
