期刊
CLINICAL GENETICS
卷 79, 期 3, 页码 199-206出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1399-0004.2010.01535.x
关键词
genome-wide association studies (GWAS); minor allele frequency (MAF); negative selection; single-nucleotide polymorphisms (SNPs)
资金
- David H. Koch Center for Applied Research of Genitourinary Cancers
- NIH [1 P50 CA140388-01, R03 CA133885, R01 CA127219, R01 CA070759, R01 CA133996-01, P01 CA34936]
- NIH Cancer Center [5 P30 CA16672]
The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.
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