Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

Abstract

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.

Keywords: GWAS; complex trait disease; nonsynonymous; protein structure.

Figure 1

Fraction of loci containing putative high impact missense (red bars) and any missense SNPs (blue bars) for each of the seven diseases. The fraction of high impact SNPs varies widely.

Figure 2

Distribution of D′ and r² for the high impact candidate missense SNPs. Most high impact SNPs have high D′ values, but small r².

Figure 3

Distribution of odds ratio of risk alleles of high impact missense SNPs. Most odds ratios are reasonably small, with 51% less than 2.

Figure 4

Examples of proposed high impact missense SNPs involved in complex trait disease mechanism. (a) Crohn’s Disease candidate SNP in MST1 (Macrophage stimulating protein) (green chain), resulting in reduced binding affinity to the RON receptor (cyan) and so reduced macrophage signaling. The ARG 703 (yellow) substitution by CYS (purple) lies close to the protein-protein interface (modeled from the hetero complex, PDB ID: 4QT8). (b) Type 1 Diabetes and Rheumatoid Arthritis candidate SNP in PTPN22 (protein tyrosine phosphatase non-receptor type 22), weakening a protein-protein association, affecting T-cell activation. The ARG 620 (yellow) to TRP substitution in PTPN22 (cyan chain) introduces a steric clash (red disks) with W47 of the SH3 of Csk (c-src tyrosine protein kinase) (green chain) (from NMR model, PDB ID: 1JEG). (c) Coronary Artery Disease candidate SNP in ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13), reducing the level of mature protein, and hence reducing cleavage of VWF (Von Willebrand factor) and downstream processes related to plaque formation. The PRO 618 (yellow) to ALA (purple) substitution lies in the β6–β7 loop of the spacer domain (green) and interacts with the C_A domain (cyan) (modeled from PDB ID: 3GHM). (d) Type 1 Diabetes candidate SNP in IL7R (interleukin 7 receptor), putatively impairing interaction with IL7, and so affecting immune signaling. The HIS 165 (yellow) to GLU (purple) substitution affects a surface loop involved in interaction with the gamma chain of the signaling complex. (modeled from PDB ID: 3UP1). (e) Crohn’s Disease candidate SNP in PLCL1 (Phospholipase C-like 1). The VAL 667 (yellow) substitution to the bulkier ILE (purple) likely distorts the substrate binding site, affecting the catalytic efficiency (modeled from PDB ID: 1DJX). (f) Type 1 Diabetes candidate SNP in SIRPB1 (signal regulatory protein beta 1) involved in immune regulation. The ILE 229 (yellow) substitution by bulkier MET (purple) results in destabilization of the protein structure (PDB ID: 2WNG). The exact role of this protein immune regulation is not yet clear. (g) Hypertension candidate SNP in TUBB1 (tubulin beta 1, class VI) related to Coronary Syndrome and Myocardial Infarction. The GLU 43 (yellow) to PRO (purple) substitution results in predicted destabilization of the protein structure through loss of polar-polar residue interactions, expected to result in lower in vivo concentration (modeled from PDB ID: 3RYC). (h) Rheumatoid Arthritis candidate SNP in INHBC (inhibin, beta C), related to the serum uric acid level. Substitution of ARG 322 (yellow) by GLN (purple) in INHBC (inhibin, beta C) is predicted to destabilize the protein structure through loss of salt bridges (red broken lines) with a spatially close conserved aspartic acid, expected to result in lower in vivo concentration (modeled from PDB ID: 2ARV).

Figure 5

Workflow for the identification of candidate high impact msSNPs potentially involved in disease mechanism.