Candidate genes with significant but directionally unexpected gene-level associations may provide valuable insights into seemingly promising preclinical results: for example, the protective gene-level signal for ATM in our analysis (burden test of PTVs odds ratio = 0.50, P = 0.003) contradicts previous expectations—based on insulin resistance and impaired glucose tolerance in Atm knockout mice28—that ATM loss-of-function should increase T2D risk. This evidence concerns the gene ATM and Impaired glucose tolerance.