June 9, 2009 | Lucia A. Hindorff, Praveen Sethupathy, Heather A. Junkins, Erin M. Ramos, Jayashri P. Mehta, Francis S. Collins, and Teri A. Manolio
The article discusses the potential etiologic and functional implications of genome-wide association loci (GWAS) for human diseases and traits. The authors developed an online catalog of SNP-trait associations from published GWAS studies, which includes over 500 associations across various diseases and traits. Key findings include:
1. **Descriptive Characteristics**: Reported trait/disease-associated SNPs (TASs) are common (median risk allele frequency 36%) and have modest effect sizes (median odds ratio 1.33). They are overrepresented in nonsynonymous sites and 5kb-promoter regions compared to randomly selected SNPs.
2. **Genomic Annotation Analysis**: TASs are not overrepresented in introns but are significantly depleted in intergenic regions. Only slightly more TASs are predicted to be in regions under positive selection.
3. **Functional Analysis**: Nonsynonymous TASs are significantly enriched in functional annotation sets, particularly those predicted to be potentially deleterious. Promoter regions also show significant enrichment, while intergenic regions are significantly depleted.
4. **Evolutionary Analysis**: A small proportion of TASs show evidence of recent positive selection, including those associated with melanin synthesis, immune response, and cancer. The risk allele of rs1121980 in the fat mass and obesity associated gene (FTO) is an attractive candidate for a "thrifty gene."
The study highlights the distribution of promising SNP-trait associations across various traits of public health interest and suggests that noncoding SNPs may play a greater role in common diseases than previously thought. The findings contribute to a more complete understanding of the contribution of common genetic variation to complex diseases.The article discusses the potential etiologic and functional implications of genome-wide association loci (GWAS) for human diseases and traits. The authors developed an online catalog of SNP-trait associations from published GWAS studies, which includes over 500 associations across various diseases and traits. Key findings include:
1. **Descriptive Characteristics**: Reported trait/disease-associated SNPs (TASs) are common (median risk allele frequency 36%) and have modest effect sizes (median odds ratio 1.33). They are overrepresented in nonsynonymous sites and 5kb-promoter regions compared to randomly selected SNPs.
2. **Genomic Annotation Analysis**: TASs are not overrepresented in introns but are significantly depleted in intergenic regions. Only slightly more TASs are predicted to be in regions under positive selection.
3. **Functional Analysis**: Nonsynonymous TASs are significantly enriched in functional annotation sets, particularly those predicted to be potentially deleterious. Promoter regions also show significant enrichment, while intergenic regions are significantly depleted.
4. **Evolutionary Analysis**: A small proportion of TASs show evidence of recent positive selection, including those associated with melanin synthesis, immune response, and cancer. The risk allele of rs1121980 in the fat mass and obesity associated gene (FTO) is an attractive candidate for a "thrifty gene."
The study highlights the distribution of promising SNP-trait associations across various traits of public health interest and suggests that noncoding SNPs may play a greater role in common diseases than previously thought. The findings contribute to a more complete understanding of the contribution of common genetic variation to complex diseases.