Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types
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Abstract
Most autoimmune-disease-risk effects identified by genome-wide association studies (GWAS) localize to open chromatin with gene-regulatory activity. GWAS loci are also enriched in expression quantitative trait loci (eQTLs), thus suggesting that most risk variants alter gene expression. However, because causal variants are difficult to identify, and cis-eQTLs occur frequently, it remains challenging to identify specific instances of disease-relevant changes to gene regulation. Here, we used a novel joint likelihood framework with higher resolution than that of previous methods to identify loci where autoimmune-disease risk and an eQTL are driven by a single shared genetic effect. Using eQTLs from three major immune subpopulations, we found shared effects in only ∼25% of the loci examined. Thus, we show that a fraction of gene-regulatory changes suggest strong mechanistic hypotheses for disease risk, but we conclude that most risk mechanisms are not likely to involve changes in basal gene expression.
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In only 14/56 loci could evidence be found that an expression quantitative trait locus and the multiple sclerosis risk effect were driven by the same underlying signal, with the remainder showing strong evidence that the genetic effects are distinct for eQTL and disease risk.
“However, in only 14/56 loci could we find evidence that an eQTL and the MS risk effect were driven by the same underlying signal, with the remainder showing strong evidence that the genetic effects are distinct for eQTL and disease risk.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [63]
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Experimental — accuracy not yet measuredFor 11/14 loci, matches were found in CD4+ T cells.
“For 11/14 loci, we found matches in CD4+ T cells, confirming the central role played by these cells in MS pathogenesis.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [63]
The main text (page unavailable) reports several multiple-sclerosis-associated loci with shared eQTL effects in CD4+ T cells. It does not report matches at 11 of 14 loci; the citing sentence describes those as the citing authors’ own findings, so that count cannot be verified from this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe 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 [63]
The paper’s main text (page unavailable) links autoimmune-disease GWAS risk to regulatory regions, including enhancers active in stimulated T cells, and examines multiple sclerosis among the diseases studied. It does not establish that the vast majority of multiple-sclerosis GWAS loci encode genes obviously active in the immune system; it says the associations are primarily non-coding and that specific disease-relevant regulatory effects are difficult to identify. The separate citation following the lymphocyte-lineage phrase is not assessed here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAn eQTL for ankyrin D55 in CD4+ T cells colocalises with GWAS signals for MS, rheumatoid arthritis and Crohn's disease.
“an eQTL for ankyrin D55 in CD4+ T cells colocalising with GWAS signals for MS, rheumatoid arthritis and Crohn's disease63”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [63]
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- Authors
- Chun, S., Casparino, A., Patsopoulos, N. A., Croteau-Chonka, D. C., Raby, B. A., De Jager, P. L., Sunyaev, S. R., & Cotsapas, C.
- Affiliations
- Broad Institute (US)
- Yale University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Sunyaev, Shamil R
- Cotsapas, Chris
- ORCID
- Venue
- Nature Genetics
- Published
- 2017-02-20
- Volume
- 49
- Issue
- 4
- Pages
- 600-605
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5374036
- OpenAlex
- W2590321928
- Cited by
- 259
- References
- 48
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 44 · 2023: 26 · 2022: 32 · 2021: 26 · 2020: 21 · 2019: 22 · 2018: 22 · 2017: 21
- FWCI
- 15.61
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (UL1TR001863)
- National Institute of Mental Health (R01MH084676, R01MH101244)
- National Human Genome Research Institute (U01HG009088)
- National Institute of General Medical Sciences (R01GM105857, R01GM078598)
- National Center for Advancing Translational Sciences
- 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 › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- expression quantitative trait loci, autoimmune disease, shared genetic effects, immune cell gene expression, open chromatin, gene expression regulation, disease risk variants, cis-eQTL, causal variants
- MeSH terms
- Autoimmune Diseases, Humans, Immunity, Gene Expression, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Gene Regulatory Networks, Genome-Wide Association Study
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