Background There are substantial differences in the clinical presentation of type 1 diabetes (T1D) depending on the first-developing autoantibody, although the underlying mechanisms are poorly understood. The DR3-DQ2 (DR3) and DR4-DQ8 (DR4) haplotypes at the MHC locus closely associate with GAD and IAA as the first-developing autoantibody, respectively, and can therefore be used as proxies for first autoantibody development in large cohort studies of T1D cases and controls.

Methods We performed the first genome-wide association study of T1D stratified by DR3 and DR4 status using 9,091 T1D cases and 14,157 controls from multiple cohorts. We estimated heritability and genetic correlation between DR3-T1D and DR4-T1D, and with other immune and glycaemic phenotypes. We assessed heterogeneity in effects on T1D between DR3 and DR4 individuals at known T1D loci. We determined enrichment of T1D heritability in DR3 and DR4 among variants in cell type-specific cis-regulatory elements (cREs) and biological pathways, and annotated risk variants in cREs.

Results We observed only moderate genetic correlation between DR4- and DR3-T1D (rg=0.6), which was lower compared to stratifications based on age of onset and sex, and distinct patterns of genetic correlations with other autoimmune diseases. Among T1D-associated loci, the IL2 locus had significantly larger effect on T1D in DR4 while several other loci (TAGAP, KLRG1) had more nominal heterogeneity. There was stronger enrichment of DR4-T1D associated variants in T cell cREs and T cell-related pathways, while DR3-T1D associated variants were specifically enriched in mast cell cREs. We finally prioritized specific loci annotated in mast cells with stronger effects on T1D in DR3 individuals.

Conclusion We performed the first GWAS of T1D stratified by DR3 and DR4 status, which revealed heterogeneity in genetic risk and biological mechanisms dependent on high-risk HLA background.

K.J.G has done consulting for Genentech, received honoraria from Pfizer, holds stock in Neurocrine biosciences, and his spouse is employed by Altos Labs, Inc. For the other authors no potential conflicts of interest relevant to this article were reported.

The work in this study was funded by an endowment from the University of California to KJG.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics for the DARE study was granted by the Devon and Torbay Research Ethics Committee, ref: 2002/7/118. The StartRight study was approved by the Southwest Cornwall and Plymouth NHS Research Ethics Committee (reference: 16/SW/0130). The Extremely Early Onset Type 1 Diabetes (EXE-T1D) study has ethical approval from Derby Research Ethics Committee, Derby, U.K. (IRAS project ID 228082). The EXTEND/PRB study has ethical approval from Southwest Cornwall & Plymouth NHS Research Ethics Committee, Bristol, U.K. (reference 14/SW/1089; 5-year extension following initial approval: reference 09/H0106/75). The TIGI study was approved by the Southwest-Central Bristol Research Ethics Committee (reference 13/SW/0312). The Institutional Review Board of the University of California San Diego gave ethical approval to analyze de-identified cohort data obtained from public sources such as dbGAP and EGA.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Summary statistics from genome-wide association studies will be made available in the GWAS catalogue upon publication. Data availability for previous T1D case and cohorts is provided through dbGAP and EGA. Exeter cohort clinical data can be used to identify individuals and are therefore available only through collaboration to experienced teams working on approved studies examining the mechanisms, cause, diagnosis, and treatment of diabetes and other β-cell disorders. Requests for collaboration will be considered by a steering committee after an application to the Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/). Contact by e-mail should be directed to R.A.O (R.Oramexeter.ac.uk). All requests for access to data will be responded to within 14 days.