Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

Horikoshi, M. et al. (2016) Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms. Human Molecular Genetics, 25(10), pp. 2070-2081. (doi:10.1093/hmg/ddw048) (PMID:26911676) (PMCID:PMC5062576)

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Abstract

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Young, Dr Robin
Authors: Horikoshi, M., Pasquali, L., Wiltshire, S., Huyghe, J. R., Mahajan, A., Asimit, J. L., Ferreira, T., Locke, A. E., Robertson, N. R., Wang, X., Sim, X., Fujita, H., Hara, K., Young, R., Zhang, W., Choi, S., Chen, H., Kaur, I., Takeuchi, F., Fontanillas, P., Thuillier, D., Yengo, L., Below, J. E., Tam, C. H.T., Wu, Y., Abecasis, G., Altshuler, D., Bell, G. I., Blangero, J., Burtt, N. P., Duggirala, R., Florez, J. C., Hanis, C. L., Seielstad, M., Atzmon, G., Chan, J. C.N., Ma, R. C.W., Froguel, P., Wilson, J. G., Bharadwaj, D., Dupuis, J., Meigs, J. B., Cho, Y. S., Park, T., Kooner, J. S., Chambers, J. C., Saleheen, D., Kadowaki, T., Tai, E. S., Mohlke, K. L., Cox, N. J., Ferrer, J., Zeggini, E., Kato, N., Teo, Y. Y., Boehnke, M., McCarthy, M. I., and Morris, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:23 February 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Human Molecular Genetics 25(10):2070-2081
Publisher Policy:Reproduced under a Creative Commons License

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