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)

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 > School of Health & 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