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Trust but verify

The Wellcome Trust Case Control Consortium presents associations to seven common diseases and I can't help asking, "so how have we done so far?" Judging by the reference list of the recent WTCCC paper in Nature, the results of 10 of the 13 Nature Genetics papers listed were replicated associations or reported associations replicated by this study.

In the data of the paper itself, evidence is presented that replicates the associations published in (at a quick but incomplete count) 6/17 past Nature Genetics papers, validating or revalidating 14/28 of the loci we have published. The reasons for failure are a rather uninstructive mixture. There are unimpressive p values for SNPs in common between studies that might indicate the initial report was a false positive, or signal a real population difference. There are many SNPs not used in both studies, a situation calling for comparison using proxy SNPs. Some previously reported loci are not considered in the WTCCC paper, and the status of these will have to be dug from the raw association data by dedicated meta-analysts.

Despite the awesome scale of the WTCCC scan, it is considered by many to be a hypothesis generating exercise and an accompanying Feature from Stephen Chanock, Teri Manolio and many colleagues warns of the necessity to replicate association results.

Replication is certainly powerful in the wake of such a big screen. The primary scan of nearly 500,000 SNPs across 17,000 people for seven diseases has so far resulted in evidence for 24 newly or multiply replicated common variant loci for three diseases that have been verified in just three replication papers.

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