Excellent post from Dr. Daniel MacArthur, Common copy number variation doesn’t explain much complex disease risk – but why not?:
The Wellcome Trust Case Control Consortium has just published the results of a massive survey of common, large DNA duplications and deletions (collectively termed copy number variation, or CNVs) in 16,000 patients suffering from complex diseases and 3,000 controls. The results come as no surprise, but are nonetheless disappointing: the study identified absolutely no novel CNVs associated with complex disease. Although three such variants were found to alter disease susceptibility, all three had been identified from previous studies.
The study’s findings suggests that – despite their size – common CNVs play very little role in the etiology of common, complex diseases like rheumatoid arthritis and type 2 diabetes, and researchers will have to look elsewhere to uncover the notorious “missing heritability” for these diseases.
Where to next? The field has already moved on with a new focus on rare variants, which (given the selection-based argument above) seem far more likely to yield useful findings. This year will see the launch of several very large studies taking a variety of approaches to dig into the lower end of the frequency spectrum: imputation using existing data-sets; new genome-wide association chips containing larger numbers of rare SNPs; and large-scale sequencing of candidate genes, whole exomes and even entire genomes. Rare variant discovery has already proved successful in the CNV field, and it seems likely that the next round of CNV association studies will prove enormously more fruitful than this study.
Missing heritability is a major issue. Though I guess it does science some good to have white whales to chase….