| Summary: | <p>We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in <em>MAP3K15</em> were 30% less likely to develop diabetes (<em>P</em> = 5.7 × 10<sup>−10</sup>) and had lower glycosylated hemoglobin (β = −0.14 SD units, <em>P</em> = 1.1 × 10<sup>−24</sup>). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (<em>P</em> < 0.05). Moreover, the protective effect of <em>MAP3K15</em> variants was stronger in individuals who did not carry the Latino-enriched <em>SLC16A11</em> risk haplotype (<em>P</em> = 6.0 × 10<sup>−4</sup>). Separately, we identified a Finnish-enriched <em>MAP3K15</em> protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (<em>P</em> < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating <em>MAP3K15</em> variants in the UKB, supporting this gene as a therapeutic target for diabetes.</p>
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