GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis
Sarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins.
Authors
- James Yarmolinsky (ORCID: https://orcid.org/0000-0003-4371-0873)
- Konstantinos K. Tsilidis (ORCID: https://orcid.org/0000-0002-8452-8472)
- Elizabeth V. Arkema (ORCID: https://orcid.org/0000-0002-3677-9736)
- Sizheng Steven Zhao (ORCID: https://orcid.org/0000-0002-3558-7353)
- Jie Chen (ORCID: https://orcid.org/0000-0002-4029-4192)
- Jiawei Geng (ORCID: https://orcid.org/0000-0002-7622-2692)
- Sarah Abramowitz (ORCID: https://orcid.org/0000-0001-5515-1752)
- Shuai Yuan (ORCID: https://orcid.org/0000-0001-5055-5627)
- Michael G. Levin (ORCID: https://orcid.org/0000-0002-9937-9932)
- Scott M. Damrauer (ORCID: https://orcid.org/0000-0001-8009-1632)
- Stephen Burgess (ORCID: https://orcid.org/0000-0001-5365-8760)
- Susanna C. Larsson (ORCID: https://orcid.org/0000-0003-0118-0341)
Institutions
- Uppsala University (SE)
- Central South University (CN)
- University of Ioannina (GR)
- University of Cambridge (GB)
- Manchester Academic Health Science Centre (GB)
- Karolinska Institutet (SE)
- University of Manchester (GB)
- Philadelphia VA Medical Center (US)
- MRC Biostatistics Unit (GB)
- Third Xiangya Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Imperial College London (GB)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1038/s41467-025-57829-z
- Citations
- 8
- Primary Topic
- Sarcoidosis and Beryllium Toxicity Research
- Type
- article
- Field-Weighted Citation Impact
- 9.31
Funders
- U.S. Department of Veterans Affairs
- American Heart Association
- National Institute for Health and Care Research
- Cancerfonden
- Central South University
- Hjärt-Lungfonden
- Karolinska Institutet
- Vetenskapsrådet
- Forskningsrådet om Hälsa, Arbetsliv och Välfärd
- Versus Arthritis
- National Institutes of Health
- Manchester Biomedical Research Centre
- Xiangya Hospital, Central South University
- NIHR Imperial Biomedical Research Centre