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- Title
Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.
- Authors
Forgetta, Vincenzo; Manousaki, Despoina; Istomine, Roman; Ross, Stephanie; Tessier, Marie-Catherine; Marchand, Luc; Min Li; Hui-Qi Qu; Bradfield, Jonathan P.; Grant, Struan F. A.; Hakonarson, Hakon; Paterson, Andrew D.; Piccirillo, Ciriaco; Polychronakos, Constantin; Richards, J. Brent; Li, Min; Qu, Hui-Qi; DCCT/EDIC Research Group
- Abstract
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.
- Subjects
RESEARCH; SEQUENCE analysis; RESEARCH methodology; ALLELES; TYPE 1 diabetes; GENETIC polymorphisms; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; DISEASE susceptibility; GENOTYPES; GENES
- Publication
Diabetes, 2020, Vol 69, Issue 4, p784
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-0831