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

Horikoshi, Momoko, Pasquali, Lorenzo, Wiltshire, Steven, Huyghe, Jeroen R., Mahajan, Anubha, Asimit, Jennifer L., Ferreira, Teresa, Locke, Adam E., Robertson, Neil R., Wang, Xu, 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 H. T., 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 C. N., Ma, Ronald C. W., 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: 2070-2081. doi:10.1093/hmg/ddw048

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Author Horikoshi, Momoko
Pasquali, Lorenzo
Wiltshire, Steven
Huyghe, Jeroen R.
Mahajan, Anubha
Asimit, Jennifer L.
Ferreira, Teresa
Locke, Adam E.
Robertson, Neil R.
Wang, Xu
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 H. T.
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 C. N.
Ma, Ronald C. W.
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.
Morris, Andrew P.
Title Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
Publication date 2016-05-01
Year available 2016
Sub-type Article (original research)
DOI 10.1093/hmg/ddw048
Open Access Status DOI
Volume 25
Issue 10
Start page 2070
End page 2081
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted 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.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G51
CUHK 1/04C
KAKENHI 23710228
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
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