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

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Horikoshi, Momoko, Pasquali, Lorenzo, Wiltshire, Steven, Huyghe, Jeroen R, Mahajan, Anubha, Asimit, Jennifer L, Ferreira, Teresa, Locke, Adam E, Robertson, Neil R, Wang, Xu et al (show 48 more authors) , Sim, Xueling, Fujita, Hayato, Hara, Kazuo, Young, Robin, Zhang, Weihua, Choi, Sungkyoung, Chen, Han, Kaur, Ismeet, Takeuchi, Fumihiko, Fontanillas, Pierre, Thuillier, Dorothee, Yengo, Loic, Below, Jennifer E, Tam, Claudia HT, Wu, Ying, Abecasis, Goncalo, Altshuler, David, Bell, Graeme I, Blangero, John, Burtt, Noel P, Duggirala, Ravindranath, Florez, Jose C, Hanis, Craig L, Seielstad, Mark, Atzmon, Gil, Chan, Juliana CN, Ma, Ronald CW, Froguel, Philippe, Wilson, James G, Bharadwaj, Dwaipayan, Dupuis, Josee, Meigs, James B, Cho, Yoon Shin, Park, Taesung, Kooner, Jaspal S, Chambers, John C, Saleheen, Danish, Kadowaki, Takashi, Tai, E Shyong, Mohlke, Karen L, Cox, Nancy J, Ferrer, Jorge, Zeggini, Eleftheria, Kato, Norihiro, Teo, Yik Ying, Boehnke, Michael, McCarthy, Mark I and Morris, Andrew P (2016) Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms. HUMAN MOLECULAR GENETICS, 25 (10). pp. 2070-2081.

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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:	Article
Uncontrolled Keywords:	T2D-GENES Consortium, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, tRNA Methyltransferases, RNA-Binding Proteins, Chromosome Mapping, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Female, Male, Cyclin-Dependent Kinase Inhibitor p16, Regulatory Elements, Transcriptional, Cyclin-Dependent Kinase Inhibitor p18, KCNQ1 Potassium Channel, Genetic Association Studies, Asian People, White People, Black or African American
Depositing User:	Symplectic Admin
Date Deposited:	22 Jun 2016 08:50
Last Modified:	13 Feb 2023 22:20
DOI:	10.1093/hmg/ddw048
Open Access URL:	http://hmg.oxfordjournals.org/content/early/2016/0...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3001808