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SNP judgments and freedom of association.

Genetic association studies using single nucleotide polymorphisms (SNPs) and insertion/deletion variants are a common feature on the atherosclerosis research landscape. A recent Medline search using the terms “[gene] AND [polymorphism] AND [X],” where X was “atherosclerosis,” “vascular biology,” thrombosis, ” or “lipoprotein,” found >4000 original articles. Furthermore, the yearly number of new reports has been growing exponentially since 1983 (Figure). The allure of SNPs, the release of millions of SNP-based markers from dedicated consortia, and the availability of cost-effective high-throughput detection methods are converging to create a potential explosion of genetic association studies in atherosclerosis. Although the standards and quality seem to be improving, there is nevertheless a risk that SNP-based association analyses will squander academic trust and scientific resources owing to unsatisfactory design and/or analysis. 



The figure shows the results of a recent Medline search using the terms “[gene] AND [polymorphism] AND [X],”, where X was “ atherosclerosis,” “vascular biology,” “thrombosis, ” or “lipoprotein.” The number of articles published each year for each combination of search terms is plotted.



Like all experimental designs and model systems, genetic association studies in human samples have strengths and limitations.1–3⇓⇓ Their potential strengths include the simplicity of design, ease of noninvasive sampling, reliability and cost-effectiveness of genotyping, uncomplicated statistical analysis, and the potential for clear interpretation and direct relevance to human biology. But many factors collude to undermine confidence in association studies. Often the initial publication of a positive association is followed by reports of non-replication or refutation. There can be good reasons for non-replication, including complexity of mechanisms, multiplicity of causative genes, confounding by gene-environment interactions, and context-dependency of the associations. However, the pattern of non-replication of genetic associations is frequent, familiar, and disconcerting. An index of the tenuous nature of genetic associations in atherosclerosis is that few DNA …