Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies.
Recent genome-wide association studies (GWAS) have led to the reliable identification of single nucleotide polymorphisms (SNPs) at a number of loci associated with increased risk of specific common human diseases. Each such locus implicates multiple possible candidate SNPs for involvement in disease mechanism. A variety of mechanisms may link the presence of an SNP to altered in vivo gene product function and hence contribute to disease risk. Here, we report an analysis of the role of one of these mechanisms, missense SNPs (msSNPs) in proteins in seven complex trait diseases. Linkage disequilibrium information was used to identify possible candidate msSNPs associated with increased disease risk at each of 356 loci for the seven diseases. Two computational methods were used to estimate which of these SNPs has a significant impact on in vivo protein function. 69% of the loci have at least one candidate msSNP and 33% have at least one predicted high-impact msSNP. In some cases, these SNPs are in well-established disease-related proteins, such as MST1 (macrophage stimulating 1) for Crohn's disease. In others, they are in proteins identified by GWAS as likely candidates for disease relevance, but previously without known mechanism, such as ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) for coronary artery disease. In still other cases, the missense SNPs are in proteins not previously suggested as disease candidates, such as TUBB1 (tubulin, beta 1, class VI) for hypertension. Together, these data support a substantial role for this class of SNPs in susceptibility to common human disease.
Institute for Bioscience and Biotechnology Research, University of Maryland, 9600 Gudelsky Drive, Rockville, MD 20850, USA.
Lipika R
LR
Pal
Institute for Bioscience and Biotechnology Research, University of Maryland, 9600 Gudelsky Drive, Rockville, MD 20850, USA; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA. Electronic address: jmoult@umd.edu.
John
J
Moult
D051722:ADAM Proteins / Q000235:genetics; D000071120:ADAMTS13 Protein; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics
D011506:Proteins; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
GWAS; complex trait disease; nonsynonymous; protein structure