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Diabetes. 2020 Jan 31. pii: db190831. doi: 10.2337/db19-0831. [Epub ahead of print]

Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Author information

1
Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
2
Departments of Human Genetics.
3
Microbiology and Immunology.
4
Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Quebec, Canada.
5
Centre of Excellence in Translational Immunology (CETI), Montréal, Quebec, Canada.
6
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
7
Pediatrics, McGill University, Montreal, Quebec Canada.
8
The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
9
Research Institute of McGill University Health Centre, Child Health and Human Development Program, Montreal, Quebec, Canada.
10
Center for Applied Genomics, Divisions of.
11
Endocrinology and Diabetes and.
12
Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
13
Departments of Pediatrics, and.
14
Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
15
Genetics and Genome Biology, The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Dalla Lana School of Public Health, Toronto, Ontario, Canada.
16
Medicine.
17
Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. brent.richards@mcgill.ca.
18
Epidemiology and Biostatistics and.
19
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

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 (SNPs) 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 cases and 15,705 controls from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 cases and 9,543 controls. Our meta-analysis identified 27 independent variants outside the major histocompatibility complex, 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 to those of common variants in the INS and PTPN22 loci (ORcombined 1.97, 95% CI 1.58-2.47, Pcombined 2.9 x 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.

PMID:
32005708
DOI:
10.2337/db19-0831

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