Abstract
BackgroundThere are now over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease. At each of these loci, there must be some molecular level mechanism relevant to the disease. What are these mechanisms and how do they contribute to disease?ResultsHere we consider the roles of three primary mechanism classes: changes that directly alter protein function (missense SNPs), changes that alter transcript abundance as a consequence of variants close-by in sequence, and changes that affect splicing. Missense SNPs are divided into those predicted to have a high impact on in vivo protein function, and those with a low impact. Splicing is divided into SNPs with a direct impact on splice sites, and those with a predicted effect on auxiliary splicing signals. The analysis was based on associations found for seven complex trait diseases in the classic Wellcome Trust Case Control Consortium (WTCCC1) GWA study and subsequent studies and meta-analyses, collected from the GWAS catalog. Linkage disequilibrium information was used to identify possible candidate SNPs for involvement in disease mechanism in each of the 356 loci associated with these seven diseases. With the parameters used, we find that 76% of loci have at least of these mechanisms. Overall, except for the low incidence of direct impact on splice sites, the mechanisms are found at similar frequencies, with changes in transcript abundance the most common. But the distribution of mechanisms over diseases varies markedly, as does the fraction of loci with assigned mechanisms. Many of the implicated proteins have previously been suggested as relevant, but the specific mechanism assignments are new. In addition, a number of new disease relevant proteins are proposed.ConclusionsThe high fraction of GWAS loci with proposed mechanisms suggests that these classes of mechanism play a major role. Other mechanism types, such as variants affecting expression of genes remote in the DNA sequence, will contribute in other loci. Each of the identified putative mechanisms provides a hypothesis for further investigation.
Highlights
There are over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease
We estimate the contribution of five molecular mechanisms falling into three major classes - missense SNPs that directly affect protein function, SNPs that alter expression level, and SNPs that may affect splicing
GWAS loci and candidate SNPs We collected disease associated markers for 356 loci for the seven complex trait diseases included in the WTCCC1 study [27], and subsequent studies and meta-analyses of these as accessed from the GWAS catalog (Table 1)
Summary
There are over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease. At each of these loci, there must be some molecular level mechanism relevant to the disease. Most information has been obtained through genome wide association studies (GWAS) linking common single nucleotide variants (the single nucleotide polymorphisms, SNPs) to disease risk. An important step in exploiting the data is to search for mechanisms that link the presence of a SNP to altered in vivo gene product function, and contribute to disease risk. We estimate the contribution of five molecular mechanisms falling into three major classes - missense SNPs that directly affect protein function (subdivided into those predicted to have a high impact and those predicted to have a lower impact), SNPs that alter expression level, and SNPs that may affect splicing (subdivided into those directly affecting splice sites and those acting through auxiliary splicing signals)
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