The UK Biobank (UKB) offers an unprecedented opportunity to assess the contribution of both common and rare genetic variation to thousands of human traits and diseases1,2,9–13. Testing for the association between rare variants and phenotypes is typically performed at the variant or gene level. Gene-level association tests include collapsing analyses and burden tests, among others14–17. Collapsing analyses are particularly well suited to detect genetic risk for phenotypes driven by an allelic series16–23 and can provide a clear link between the causal gene and phenotype. Applications of these methods to the first 50,000 UKB exome sequences have indicated an important role of rare variation in complex disease but have also highlighted a need for larger sample sizes10,11.
