Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes Journal Articles uri icon

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  • Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with Preplication < 0.05 and Pcombined < Pdiscovery. In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of STK39, with an effect size comparable with those of common variants in the INS and PTPN22 loci (combined [from the discovery and replication cohorts] estimate of odds ratio [ORcombined] 1.97, 95% CI 1.58–2.47, Pcombined = 2.9 × 10−9). Pharmacological inhibition of Stk39 activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.


  • Forgetta, Vincenzo
  • Manousaki, Despoina
  • Istomine, Roman
  • Ross, Stephanie
  • Tessier, Marie-Catherine
  • Marchand, Luc
  • Li, Min
  • Qu, Hui-Qi
  • Bradfield, Jonathan P
  • Grant, Struan FA
  • Hakonarson, Hakon
  • Paterson, Andrew D
  • Piccirillo, Ciriaco
  • Polychronakos, Constantin
  • Richards, J Brent

publication date

  • April 1, 2020