Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis
Open accessAbstract
Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.
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By 2011, common variants in 26 genomic loci had been associated with multiple sclerosis risk and independently replicated.
“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 [36]
The Introduction (page unavailable) identifies several MS susceptibility genes, including IL2RA, CD58, CLEC16A and EVI5, as independently replicated. It does not report 26 replicated genomic loci or establish a count as of 2011; the Results (page unavailable) also caution that this study lacked full-scale independent replication. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeveral studies have explored the genetic basis of clinical course, age of onset and severity, although no genome-wide significant associations have been discovered.
“Several studies have explored the genetic basis of clinical course, age of onset and severity, although no genome‐wide significant associations have been discovered.36, 37, 43, 74, 75, 76, 77”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [36]
The Introduction describes earlier studies of genetic influences on MS severity and clinical course, and the genotype–phenotype analysis section says this study assessed age of onset and the severity metric MSSS. The cited passages do not establish the broader claim that no genome-wide significant associations had been discovered; the Discussion reports significant phenotype associations without stating whether they met a genome-wide threshold. Page numbers are unavailable in our copy. (LLM, conf=0.78)
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- Authors
- Baranzini, S. E., Wang, J., Gibson, R. A., Galwey, N., Naegelin, Y., Barkhof, F., Radue, E.-W., Lindberg, R. L. P., Uitdehaag, B. M. G., Johnson, M. R., Angelakopoulou, A., Hall, L., Richardson, J. C., Prinjha, R. K., Gass, A., Geurts, J. J. G., Kragt, J., Sombekke, M., Vrenken, H., Qualley, P., Lincoln, R. R., Gomez, R., Caillier, S. J., George, M. F., Mousavi, H., Guerrero, R., Okuda, D. T., Cree, B. A. C., Green, A. J., Waubant, E., Goodin, D. S., Pelletier, D., Matthews, P. M., Hauser, S. L., Kappos, L., Polman, C. H., & Oksenberg, J. R.
- Affiliations
- University of California, San Francisco (US)
- GlaxoSmithKline (United Kingdom) (GB)
- University of Basel (CH)
- Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Oksenberg, Jorge R.
- ORCID
- Baranzini, Sergio E.
- Wang, Joanne
- Gibson, Rachel A.
- Galwey, Nicholas
- Naegelin, Yvonne
- Barkhof, Frederik
- Lindberg, Raija L.P.
- Johnson, Michael R.
- Richardson, Jill C.
- Prinjha, Rab K.
- Gass, Achim
- Geurts, Jeroen J.G.
- Vrenken, Hugo
- Lincoln, Robin R.
- Gomez, Refujia
- Caillier, Stacy J.
- George, Michaela F.
- Guerrero, Rosa
- Okuda, Darin T.
- Cree, Bruce A. C.
- Green, Ari J.
- Waubant, Emmanuelle
- Goodin, Douglas S.
- Matthews, Paul M.
- Hauser, Stephen L.
- Kappos, Ludwig
- Polman, Chris H.
- Oksenberg, Jorge R.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-11-14
- Volume
- 18
- Issue
- 4
- Pages
- 767-778
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4334814
- OpenAlex
- W2103649136
- Cited by
- 476
- References
- 7
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 16 · 2023: 14 · 2022: 12 · 2021: 16 · 2020: 25 · 2019: 24 · 2018: 23 · 2017: 24 · 2016: 21 · 2015: 29 · 2014: 39 · 2013: 54 · 2012: 33
- FWCI
- 31.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Dominican Scholar (Dominican University of California) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS026799)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- multiple sclerosis, genetic susceptibility, single nucleotide polymorphisms, age of onset, disease severity, brain volume, MHC locus, chromosome 6p21.3, GPC5, heparan sulfate proteoglycans, clinical phenotype, gene ontology functional classification
- MeSH terms
- Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Multiple Sclerosis, Phenotype, Prospective Studies, Case-Control Studies, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Glypicans, Genome-Wide Association Study, Young Adult
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