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Regulatory polymorphisms underlying complex disease traits.
Open accessAbstract
There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.
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“genes with local eQTL are promising candidates for underlying disease-associated regions in human GWAS studies (Knight 2005; Chen et al. 2008; Emilsson et al. 2008; Musunuru et al. 2010; Hou and Zhao 2013; Li et al. 2013).”
From RNA-Seq Alignment to Individualized Genomes Improves Transcript Abundance Estimates in Multiparent Populations (2014) · cites this paper as Knight 2005
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Metadata
- Authors
- Knight, J. C.
- Affiliations
- Centre for Human Genetics (GB)
- Corresponding author
- Knight, Julian C.
- ORCID
- Knight, Julian C.
- Venue
- Journal of Molecular Medicine
- Published
- 2004-12-09
- Volume
- 83
- Issue
- 2
- Pages
- 97-109
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC3132451
- OpenAlex
- W2143162176
- Cited by
- 246
- References
- 130
- Citations by year
- 2026: 2 · 2025: 2 · 2022: 5 · 2021: 8 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 11 · 2015: 7 · 2014: 10 · 2013: 12 · 2012: 23
- FWCI
- 10.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (074318)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- regulatory polymorphisms, complex disease susceptibility, expression quantitative trait loci, allele-specific expression, linkage disequilibrium, type 1 diabetes, CTLA-4, autoimmune disease, factor VII deficiency, ischemic heart disease, Duffy binding protein, malaria, CCR5, HIV-1 infection, transcriptional regulation, splicing regulation, CD45, translation efficiency, F12, heritability of gene expression
- MeSH terms
- Autoimmune Diseases, Diabetes Mellitus, Gene Expression Regulation, Humans, Polymorphism, Genetic, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Tumor Necrosis Factors
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