Volume 12 Supplement 1

Beyond the Genome 2011

Open Access

Genetic basis of common human disease: insight into the role of nonsynonymous SNPs from genome-wide association studies

  • Lipika R Pal1 and
  • John Moult1, 2
Genome Biology201112(Suppl 1):P10

https://doi.org/10.1186/gb-2011-12-s1-p10

Published: 19 September 2011

Background

Recent genome-wide association studies have led to the reliable identification of single nucleotide polymorphisms (SNPs) at a number of loci associated with an increased risk of developing specific common human diseases. Each such locus implicates multiple possible candidate SNPs as being involved in the disease mechanism, and determining which SNPs actually contribute, and by what mechanism, is a major challenge. A variety of mechanisms may link the presence of a SNP to altered in vivo gene product function and hence contribute to disease risk. We have analyzed the role of one of these mechanisms, nonsynonymous SNPs (nsSNPs) in proteins, for associations found in the Wellcome Trust Case-Control Consortium (WTCCC) study of seven common diseases [1] and the follow-up work.

Methods

Using HapMap data and linkage disequilibrium information, we identified all possible candidate SNPs associated with increased disease risk. We then applied two computational methods [2, 3], based on analysis of protein structure and sequence, to determine which of these SNPs has a significant impact on in vivo protein function (SNPs3D) [4].

Results

Several of these disease-associated loci were found to be linked to one or more high-impact nsSNPs. In some cases, these SNPs are in well-known proteins (such as human leukocyte antigens). In other cases, they are in less well-established disease-associated genes (for example, MST1 for Crohn’s disease), and in yet others, they are in proteins that have been poorly investigated (for example, gasdermin B, also for Crohn’s disease). Approximately 55% of these disease-associated loci have at least one nsSNP, and about 33% of them have at least one high-impact nsSNP in those regions.

Conclusions

Together, these data suggest a significant role for nsSNPs in common human disease susceptibility.

Authors’ Affiliations

(1)
Institute for Bioscience and Biotechnology Research, University of Maryland at College Park
(2)
Department of Cell Biology and Molecular Genetics, University of Maryland at College Park

References

  1. Wellcome Trust Case-Control Consortium: Genome wide association study of 14000 cases of seven common diseases and 3,000 shared controls. Nature. 2007, 447: 661-678. 10.1038/nature05911.View ArticleGoogle Scholar
  2. Yue P, Li Z, Moult J: Loss of protein structure stability as a major causative factor in monogenic disease. J Mol Biol. 2005, 353: 459-473. 10.1016/j.jmb.2005.08.020.PubMedView ArticleGoogle Scholar
  3. Yue P, Moult J: Identification and analysis of deleterious human SNPs. J Mol Biol. 2006, 356: 1263-1274. 10.1016/j.jmb.2005.12.025.PubMedView ArticleGoogle Scholar
  4. SNPs3D Project. [http://www.snps3d.org]

Copyright

© Pal and Moult; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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