Forgetta V, Manousaki D, Istomine R, et al. - Given that most replicated genetic determinants for T1D are common (minor allele frequency [MAF] > 5%), researchers identified novel rare or low-frequency (MAF < 5%) single nucleotide polymorphisms (SNPs) with large effects on risk of T1D. They conducted deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 T1D cases and 15,705 controls from 12 European cohorts. Twenty-seven independent variants outside the major histocompatibility complex were identified, among which 3 were novel and had MAF < 5%. In primary murine T cells, pharmacological inhibition of STK39 activity augmented effector responses by enhancement of interleukin 2 signaling. Such results provide insight into the genetic architecture of T1D and have identified unusual variants that have a significant effect on disease risk.