Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Johnny S.H. Kwan; Yi Hsiang Hsu; Ching Lung Cheung; Josée Dupuis; Aude Saint-Pierre; Joel Eriksson; Samuel K. Handelman; Aaron Aragaki; David Karasik; Peter P. Pramstaller; Charles Kooperberg; Andrea Z. Lacroix; Martin G. Larson; Kam Shing Lau; Mattias Lorentzon; Irene Pichler; Pak C. Sham; Daniel Taliun; Liesbeth Vandenput; Douglas P. Kiel; Andrew A. Hicks; Rebecca D. Jackson; Claes Ohlsson; Emelia J. Benjamin; Annie W.C. Kung

doi:10.1093/hmg/ddu386

Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Johnny S.H. Kwan, Yi Hsiang Hsu, Ching Lung Cheung, Josée Dupuis, Aude Saint-Pierre, Joel Eriksson, Samuel K. Handelman, Aaron Aragaki, David Karasik, Peter P. Pramstaller, Charles Kooperberg, Andrea Z. Lacroix, Martin G. Larson, Kam Shing Lau, Mattias Lorentzon, Irene Pichler, Pak C. Sham, Daniel Taliun, Liesbeth Vandenput, Douglas P. KielAndrew A. Hicks, Rebecca D. Jackson, Claes Ohlsson, Emelia J. Benjamin, Annie W.C. Kung

University of Lübeck

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

Original language	English
Pages (from-to)	6684-6693
Number of pages	10
Journal	Human Molecular Genetics
Volume	23
Issue number	24
DOIs	https://doi.org/10.1093/hmg/ddu386
State	Published - 15 Dec 2014
Externally published	Yes

Bibliographical note

Publisher Copyright:
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Funding

This work was supported by the Hong Kong Research Grant Council; the Small Project Funding HKU 201309176244 and 201109176063; the Bone Health Fund of HKU Foundation and Matching Grant; the CRCG Grant and the Osteoporosis Research Fund of The University of Hong Kong. The GOOD study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, COMBINE, the ALF/LUA research grant from the Sahlgrenska University Hospital, the LundbergFoundation,theTorstenandRagnarSöderberg´sFoun-dation, the Novo Nordisk Foundation, the Gustav V and Queen Victoria Freemason Foundation and the European Commission Grant HEALTH-F2 – 2008-201865-GEFOS. The Framingham Heart Study of the NHLBI, NIH and Boston University School of Medicine were supported by the NHLBI’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). The WHI work was supported in part by an allocation of computing time from the Ohio Supercomputer Center and the National Institute of General Medical Sciences (U01GM092655) as well as HHSN268201100002C, NO1-6H74316, U54RR0024384 and HHSN268200960002C. The MICROS study was supported by the Ministry of Health and Department for Promotion of Educational Policies, Universities and Research of the Autonomous Province of Bolzano, South Tyrol, the South Tyrolean Sparkasse Foundation, and the European Union Framework Program 6 EUROSPAN Project (contract no. LSHG-CT-2006-018947). In addition, D.P.K. received support from NIH (Grant R01 AR/AG 41398). E.J.B. received support from the FHS grants 1RO1HL64753, R01HL076784, 1 R01AG028321 and 2R01H L092577.

Funders	Funder number
Bone Health Fund of HKU Foundation
Department for Promotion of Educational Policies, Universities and Research of the Autonomous Province of Bolzano, South Tyrol
Osteoporosis Research Fund of The University of Hong Kong
Queen Victoria Freemason Foundation
South Tyrolean Sparkasse Foundation
National Institutes of Health	N02-HL-6-4278, N01-HC-25195
National Heart, Lung, and Blood Institute	R01HL076784
National Institute of General Medical Sciences	U54RR0024384, U01GM092655, HHSN268201100002C, HHSN268200960002C, NO1-6H74316
Ministry of Health
Sixth Framework Programme	R01 AR/AG 41398, LSHG-CT-2006-018947
Framingham Heart Study	1RO1HL64753, R01AG028321, 2R01H L092577
Ohio Supercomputer Center
European Commission	HEALTH-F2 – 2008-201865-GEFOS
Stiftelsen för Strategisk Forskning
Research Grants Council, University Grants Committee	201109176063, HKU 201309176244
Vetenskapsrådet
Sahlgrenska Universitetssjukhuset
Novo Nordisk Fonden

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kwan, J. S. H., Hsu, Y. H., Cheung, C. L., Dupuis, J., Saint-Pierre, A., Eriksson, J., Handelman, S. K., Aragaki, A., Karasik, D., Pramstaller, P. P., Kooperberg, C., Lacroix, A. Z., Larson, M. G., Lau, K. S., Lorentzon, M., Pichler, I., Sham, P. C., Taliun, D., Vandenput, L., ... Kung, A. W. C. (2014). Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels. Human Molecular Genetics, 23(24), 6684-6693. https://doi.org/10.1093/hmg/ddu386

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abstract = "Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.",

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Kwan, JSH, Hsu, YH, Cheung, CL, Dupuis, J, Saint-Pierre, A, Eriksson, J, Handelman, SK, Aragaki, A, Karasik, D, Pramstaller, PP, Kooperberg, C, Lacroix, AZ, Larson, MG, Lau, KS, Lorentzon, M, Pichler, I, Sham, PC, Taliun, D, Vandenput, L, Kiel, DP, Hicks, AA, Jackson, RD, Ohlsson, C, Benjamin, EJ & Kung, AWC 2014, 'Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels', Human Molecular Genetics, vol. 23, no. 24, pp. 6684-6693. https://doi.org/10.1093/hmg/ddu386

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AU - Kwan, Johnny S.H.

AU - Hsu, Yi Hsiang

AU - Cheung, Ching Lung

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AU - Saint-Pierre, Aude

AU - Eriksson, Joel

AU - Handelman, Samuel K.

AU - Aragaki, Aaron

AU - Karasik, David

AU - Pramstaller, Peter P.

AU - Kooperberg, Charles

AU - Lacroix, Andrea Z.

AU - Larson, Martin G.

AU - Lau, Kam Shing

AU - Lorentzon, Mattias

AU - Pichler, Irene

AU - Sham, Pak C.

AU - Taliun, Daniel

AU - Vandenput, Liesbeth

AU - Kiel, Douglas P.

AU - Hicks, Andrew A.

AU - Jackson, Rebecca D.

AU - Ohlsson, Claes

AU - Benjamin, Emelia J.

AU - Kung, Annie W.C.

PY - 2014/12/15

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AB - Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

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Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Abstract

Bibliographical note

Funding

UN SDGs

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