Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS One. 2010 Oct 22;5(10):e13574. doi: 10.1371/journal.pone.0013574.
Many DNA variants have been identified on more than 300 diseases and traits using Genome-Wide Association Studies (GWASs). Some have been validated using deep sequencing, but many fewer have been validated functionally, primarily focused on non-synonymous coding SNPs (nsSNPs). It is an open question whether synonymous coding SNPs (sSNPs) and other non-coding SNPs can lead to as high odds ratios as nsSNPs. We conducted a broad survey across 21,429 disease-SNP associations curated from 2,113 publications studying human genetic association, and found that nsSNPs and sSNPs shared similar likelihood and effect size for disease association. The enrichment of disease-associated SNPs around the 80(th) base in the first introns might provide an effective way to prioritize intronic SNPs for functional studies. We further found that the likelihood of disease association was positively associated with the effect size across different types of SNPs, and SNPs in the 3' untranslated regions, such as the microRNA binding sites, might be under-investigated. Our results suggest that sSNPs are just as likely to be involved in disease mechanisms, so we recommend that sSNPs discovered from GWAS should also be examined with functional studies.
利用全基因组关联研究（GWAS），已经在 300 多种疾病和特征上鉴定出了许多 DNA 变体。其中一些已经通过深度测序进行了验证，但功能验证的要少得多，主要集中在非同义编码 SNP（nsSNP）上。同义编码 SNP（sSNP）和其他非编码 SNP 是否能像 nsSNP 一样导致高比值仍然是一个悬而未决的问题。我们对 2113 项研究人类遗传关联的出版物中整理出的 21429 个疾病-SNP 关联进行了广泛调查，发现 nsSNP 和 sSNP 在疾病关联方面具有相似的可能性和效应大小。第一内含子第 80 位碱基附近疾病相关 SNP 的富集可能为功能研究提供一种优先考虑内含子 SNP 的有效方法。我们还发现，疾病关联的可能性与不同类型 SNP 的效应大小呈正相关，而 3'非翻译区（如 microRNA 结合位点）的 SNP 可能研究不足。我们的研究结果表明，sSNP 同样可能参与疾病机制，因此我们建议也应该用功能研究来检查 GWAS 发现的 sSNP。
