Pathway and network-based analysis of genome-wide association studies in multiple sclerosis
Open accessAbstract
Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.
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Analyses of bipolar disorder provided evidence of association with hormone action and adherens junctions.
“Analyses of bipolar disorder provided evidence of association with hormone action and adherens junctions7,9,10”
From Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways (2015) · cites this paper as [7]
Pathway analysis can translate GWAS signals into biochemical and/or system-wide understanding and can provide successful replication in the presence of allelic and locus heterogeneity.
“pathway analysis can translate GWAS signals into a level of understanding that is biochemical and/or system-wide and can provide successful replication in the presence of allelic and locus heterogeneity7,8”
From Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways (2015) · cites this paper as [7]
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- Authors
- Baranzini, S. E., Galwey, N. W., Wang, J., Khankhanian, P., Lindberg, R., Pelletier, D., Wu, W., Uitdehaag, B. M. J., Kappos, L., GeneMSA Consortium, Polman, C. H., Matthews, P. M., Hauser, S. L., Gibson, R. A., Oksenberg, J. R., & Barnes, M. R.
- Affiliations
- University of California, San Francisco (US)
- GlaxoSmithKline (United Kingdom) (GB)
- University Hospital of Basel (CH)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Baranzini, S. E.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-03-13
- Volume
- 18
- Issue
- 11
- Pages
- 2078-2090
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2678928
- OpenAlex
- W2097099463
- Cited by
- 383
- References
- 50
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 15 · 2019: 23 · 2018: 15 · 2017: 18 · 2016: 36 · 2015: 28 · 2014: 33 · 2013: 46 · 2012: 30
- FWCI
- 33.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Multiple Sclerosis Society
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- multiple sclerosis, genome-wide association study, pathway analysis, protein-protein interaction network, immune pathways, cell adhesion, axon guidance, synaptic potentiation, neural pathways, disease susceptibility
- MeSH terms
- Female, Genotype, Humans, Male, Multiple Sclerosis, Signal Transduction, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Regulatory Networks, Genome-Wide Association Study
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