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Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene
Open accessAbstract
Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.
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In the citing paper
“by 2011, common variants in 26 genomic loci had been associated with MS risk and independently replicated”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [38]
In the citing paper
“One example is rs744166 (located in an intron of the STAT3 gene on chromosome 17): the G allele is associated with increased risk in MS38 and decreased risk in Crohn's disease.71”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [38]
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Metadata
- Authors
- Jakkula, E., Leppä, V., Sulonen, A.-M., Varilo, T., Kallio, S., Kemppinen, A., Purcell, S., Koivisto, K., Tienari, P., Sumelahti, M.-L., Elovaara, I., Pirttilä, T., Reunanen, M., Aromaa, A., Oturai, A. B., Søndergaard, H. B., Harbo, H. F., Mero, I.-L., Gabriel, S. B., Mirel, D. B., Hauser, S. L., Kappos, L., Polman, C., De Jager, P. L., Hafler, D. A., Daly, M. J., Palotie, A., Saarela, J., & Peltonen, L.
- Affiliations
- Broad Institute (US)
- University of Helsinki (FI)
- Seinäjoen Keskussairaala (FI)
- Tampere University (FI)
- Tampere University Hospital (FI)
- Kuopio University Hospital (FI)
- Oulu University Hospital (FI)
- Finnish Institute for Health and Welfare (FI)
- Copenhagen University Hospital (DK)
- Oslo University Hospital (NO)
- University of California, San Francisco (US)
- University of Basel (CH)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Brigham and Women's Hospital (US)
- Corresponding author
- Peltonen, Leena
- ORCID
- Jakkula, Eveliina
- Leppä, Virpi
- Sulonen, Anna-Maija
- Varilo, Teppo
- Kemppinen, Anu
- Purcell, Shaun
- Tienari, Pentti
- Sumelahti, Marja-Liisa
- Søndergaard, Helle Bach
- Harbo, Hanne F.
- Mero, Inger-Lise
- Gabriel, Stacey B.
- Hauser, Stephen L.
- Kappos, Ludwig
- Polman, Chris
- Hafler, David A.
- Daly, Mark J.
- Palotie, Aarno
- Saarela, Janna
- Peltonen, Leena
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 86
- Issue
- 2
- Pages
- 285-291
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2820168
- OpenAlex
- W2097780447
- Cited by
- 245
- References
- 56
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 17 · 2020: 15 · 2019: 14 · 2018: 13 · 2017: 11 · 2016: 12 · 2015: 19 · 2014: 25 · 2013: 29 · 2012: 16
- FWCI
- 19.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (089061/Z/09/Z)
- National Institutes of Health (6u54rr020278-06)
- National Institute of Mental Health (R01MH071425)
- National Institute of Neurological Disorders and Stroke (R01NS43559, R01NS043559)
- National Center for Research Resources (U54-RR020278)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- multiple sclerosis, genetic risk, rare variants, Finnish population, haplotypes, Crohn's disease, autoimmune disease, HLA locus
- MeSH terms
- Alleles, Genetics, Population, Haplotypes, Humans, Multiple Sclerosis, Reproducibility of Results, Linkage Disequilibrium, Case-Control Studies, Genetic Predisposition to Disease, Base Pairing, Polymorphism, Single Nucleotide, STAT3 Transcription Factor, Genome-Wide Association Study
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