Pervasive Sharing of Genetic Effects in Autoimmune Disease
Open accessAbstract
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.
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Many loci were associated with multiple diseases and the genes encoded in those loci fall into distinct immune pathways.
“many loci were associated with multiple diseases and that the genes encoded in those loci fall into distinct immune pathways.69, 70”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [70]
The Introduction reports that nearly half the loci identified for one disease influence at least two diseases. The Results find significant protein connectivity in three of four locus clusters and suggest that they represent distinct molecular mechanisms; two groups are preferentially expressed in immune-cell subtypes. The claim overstates this evidence by presenting distinct immune pathways for the genes as established rather than inferred. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPerturbations to key immune processes mediate risk to multiple diseases.
“These results suggest that perturbations to key immune processes mediate risk to multiple diseases.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [70]
Some pleiotropic relationships are expected, such as obesity variants affecting risk of hepatic steatosis and type 2 diabetes, or variants influencing multiple autoimmune conditions.
“Some of these relationships are expected, such as the impact of obesity variants on risk of hepatic steatosis and type 2 diabetes84 or variants that influence multiple autoimmune conditions85.”
From A brief history of human disease genetics (2020) · cites this paper as [85]
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Unifying immunology with informatics and multiscale biology
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The Genetics of Complex Cholestatic Disorders
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Self-citationA Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease
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- Authors
- Cotsapas, C., Voight, B. F., Rossin, E., Lage, K., Neale, B. M., Wallace, C., Abecasis, G. R., Barrett, J. C., Behrens, T., Cho, J., De Jager, P. L., Elder, J. T., Graham, R. R., Gregersen, P., Klareskog, L., Siminovitch, K. A., van Heel, D. A., Wijmenga, C., Worthington, J., Todd, J. A., Hafler, D. A., Rich, S. S., Daly, M. J., & on behalf of the FOCiS Network of Consortia
- Affiliations
- Massachusetts General Hospital (US)
- Broad Institute (US)
- University of Cambridge (GB)
- University of Michigan (US)
- Wellcome Sanger Institute (GB)
- Genentech (US)
- Yale University (US)
- Northwell Health (US)
- Karolinska Institutet (SE)
- Mount Sinai Hospital (CA)
- University Medical Center Groningen (NL)
- Manchester Academic Health Science Centre (GB)
- University of Virginia (US)
- Corresponding author
- Daly, Mark J.
- ORCID
- Cotsapas, Chris
- Voight, Benjamin F.
- Rossin, Elizabeth
- Lage, Kasper
- Neale, Benjamin M.
- Wallace, Chris
- Abecasis, Gonçalo R.
- Barrett, Jeffrey C.
- Behrens, Timothy
- Cho, Judy
- Elder, James T.
- Graham, Robert R.
- Gregersen, Peter
- Klareskog, Lars
- Wijmenga, Cisca
- Worthington, Jane
- Todd, John A.
- Hafler, David A.
- Rich, Stephen S.
- Daly, Mark J.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-10
- Volume
- 7
- Issue
- 8
- Pages
- e1002254
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3154137
- OpenAlex
- W1859891932
- Cited by
- 606
- References
- 30
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 21 · 2023: 26 · 2022: 26 · 2021: 27 · 2020: 40 · 2019: 37 · 2018: 40 · 2017: 77 · 2016: 40 · 2015: 54 · 2014: 57 · 2013: 63 · 2012: 52
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Figshare (submittedVersion, cc-by)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- PLoS eBooks
- Funders
- Wellcome Trust (091157, 089989)
- National Institute for Health and Care Research (NF-SI-0508-10275)
- Versus Arthritis (/17552)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050511, R01AR042742, R01AR054966)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- autoimmune disease, shared genetic risk, immune-mediated diseases, single nucleotide polymorphisms, celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, protein-protein interaction network, pathogenesis, MHC locus
- MeSH terms
- Autoimmune Diseases, Humans, Phenotype, Comorbidity, Cluster Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Protein Interaction Maps
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.
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