The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan1 on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9; Poverall ≤ 1.15 × 10−14), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.
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This work was funded by the Juvenile Diabetes Research Foundation International and the Wellcome Trust. We gratefully acknowledge the participation of all the patients, control subjects and family members and thank the Human Biological Data Interchange and Diabetes UK for the USA and UK multiplex families, respectively, the Norwegian Study Group for Childhood Diabetes for the collection of Norwegian families (D. Undlien and K. Rønningen), D. Savage, C. Patterson, D. Carson and P. Maxwell for the Northern Irish samples. GET1FIN (J. Tuomilehto, L. Kinnunen, E. Tuomilehto-Wolf, V. Harjutsalo and T. Valle) thank the Academy of Finland, the Sigrid Juselius Foundation and the JDRF for funding. We acknowledge use of the DNA from the 1958 British Birth Cohort collection, funded by the Medical Research Council and Wellcome Trust, and we thank D. Strachan and P. Burton for their help. We also thank The Avon Longitudinal Study of Parents and Children laboratory in Bristol, including S. Ring, R. Jones, M. Pembrey and W. McArdle for preparing and providing the control DNA samples. We thank colleagues at Affymetrix for help and advice in genotyping and T. Willis, M. Faham and P. Hardenbol for the molecular inversion probe technology. We thank the Wellcome Trust for funding the AITD UK national collection; all doctors and nurses in Birmingham, Bournemouth, Cambridge, Cardiff, Exeter, Leeds, Newcastle and Sheffield for recruitment of patients and J. Franklyn, S. Pearce (Newcastle) and P. Newby (Birmingham) for preparing and providing DNA samples on Graves' disease patients. We thank V. Everett, G. Scholz and G. Dolman for information technology support. T1D DNA samples were prepared by K. Bourget, S. Duley, M. Hardy, S. Hawkins, S. Hood, E. King, T. Mistry, A. Simpson, S. Wood, P. Lauder, S. Clayton, F. Wright and C. Collins. We thank L. Peterson for helpful discussions. C.W. is supported by the British Heart Foundation. S. Nejentsev is a Diabetes Research and Wellness Foundation Non-Clinical Fellow.
Association localization plots.
Cross-species alignment of KIAA0350.
The locus-specific sibling recurrence-risk ratio of type 1 diabetes susceptibility variants.
Type 1 diabetes association analyses of SNPs chosen for follow-up from the WTCCC and nsSNP studies in case-controls and families.
Further genotyping from the 18p11 and 12q24 regions.
A summary of geographically variable nsSNPs and association analyses in type 1 diabetes.
Graves' disease case-control association analyses.
DNA collections and references.
Concordance between the two GWA studies and TaqMan genotyping.
About this article
Variants in the BACH2 and CLEC16A gene might be associated with susceptibility to insulin‐triggered type 1 diabetes
Journal of Diabetes Investigation (2019)