Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

doi:10.1038/s41467-018-08008-w

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

College of Public Health

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Abstract

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Original language	English
Article number	376
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08008-w
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.

Funding Information:
Competing interests: Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Brenda W.J.H. Penninx has received research funding (nonrelated to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls’ participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Dr. Nalls also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and has a Commercial affiliation with Data Technica International, Glen Echo, MD, USA. Jost B. Jonas serves as a consultant for Mundipharma Co. (Cambridge, UK), patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and is patent applicant with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15,000 771.4). Paul W. Franks has been a paid consultant in the design of a personalized Nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical Companies as part of European Union Innovative Medicines Initiative (IMI) Projects. Terho Lehtimäki is employed by Fimlab Ltd. Ozren Polasek is employed by Gen-info Ltd. The remaining authors declare no competing interests.

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

Physics and Astronomy (all)
Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)

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10.1038/s41467-018-08008-w

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@article{0631f777d2af450f8d9b292a2bcfe211,

title = "Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity",

abstract = "Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.",

author = "Kilpel{\"a}inen, {Tuomas O.} and Bentley, {Amy R.} and Raymond Noordam and Sung, {Yun Ju} and Karen Schwander and Winkler, {Thomas W.} and Hermina Jakupovi{\'c} and Chasman, {Daniel I.} and Alisa Manning and Ioanna Ntalla and Hugues Aschard and Brown, {Michael R.} and {de las Fuentes}, Lisa and Nora Franceschini and Xiuqing Guo and Dina Vojinovic and Stella Aslibekyan and Feitosa, {Mary F.} and Minjung Kho and Musani, {Solomon K.} and Melissa Richard and Heming Wang and Zhe Wang and Bartz, {Traci M.} and Bielak, {Lawrence F.} and Archie Campbell and Rajkumar Dorajoo and Virginia Fisher and Hartwig, {Fernando P.} and Horimoto, {Andrea R.V.R.} and Changwei Li and Lohman, {Kurt K.} and Jonathan Marten and Xueling Sim and Smith, {Albert V.} and Tajuddin, {Salman M.} and Maris Alver and Marzyeh Amini and Mathilde Boissel and Chai, {Jin Fang} and Xu Chen and Jasmin Divers and Evangelos Evangelou and Chuan Gao and Mariaelisa Graff and Harris, {Sarah E.} and Meian He and Hsu, {Fang Chi} and Jackson, {Anne U.} and Arnett, {Donna K.}",

note = "Funding Information: The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4. Funding Information: Competing interests: Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Brenda W.J.H. Penninx has received research funding (nonrelated to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls{\textquoteright} participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Dr. Nalls also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and has a Commercial affiliation with Data Technica International, Glen Echo, MD, USA. Jost B. Jonas serves as a consultant for Mundipharma Co. (Cambridge, UK), patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and is patent applicant with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europ{\"a}ische Patentanmeldung 15,000 771.4). Paul W. Franks has been a paid consultant in the design of a personalized Nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical Companies as part of European Union Innovative Medicines Initiative (IMI) Projects. Terho Lehtim{\"a}ki is employed by Fimlab Ltd. Ozren Polasek is employed by Gen-info Ltd. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-08008-w",

language = "English",

volume = "10",

number = "1",

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TY - JOUR

T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

AU - Kilpeläinen, Tuomas O.

AU - Bentley, Amy R.

AU - Noordam, Raymond

AU - Sung, Yun Ju

AU - Schwander, Karen

AU - Winkler, Thomas W.

AU - Jakupović, Hermina

AU - Chasman, Daniel I.

AU - Manning, Alisa

AU - Ntalla, Ioanna

AU - Aschard, Hugues

AU - Brown, Michael R.

AU - de las Fuentes, Lisa

AU - Franceschini, Nora

AU - Guo, Xiuqing

AU - Vojinovic, Dina

AU - Aslibekyan, Stella

AU - Feitosa, Mary F.

AU - Kho, Minjung

AU - Musani, Solomon K.

AU - Richard, Melissa

AU - Wang, Heming

AU - Wang, Zhe

AU - Bartz, Traci M.

AU - Bielak, Lawrence F.

AU - Campbell, Archie

AU - Dorajoo, Rajkumar

AU - Fisher, Virginia

AU - Hartwig, Fernando P.

AU - Horimoto, Andrea R.V.R.

AU - Li, Changwei

AU - Lohman, Kurt K.

AU - Marten, Jonathan

AU - Sim, Xueling

AU - Smith, Albert V.

AU - Tajuddin, Salman M.

AU - Alver, Maris

AU - Amini, Marzyeh

AU - Boissel, Mathilde

AU - Chai, Jin Fang

AU - Chen, Xu

AU - Divers, Jasmin

AU - Evangelou, Evangelos

AU - Gao, Chuan

AU - Graff, Mariaelisa

AU - Harris, Sarah E.

AU - He, Meian

AU - Hsu, Fang Chi

AU - Jackson, Anne U.

AU - Arnett, Donna K.

N1 - Funding Information: The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4. Funding Information: Competing interests: Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Brenda W.J.H. Penninx has received research funding (nonrelated to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls’ participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Dr. Nalls also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and has a Commercial affiliation with Data Technica International, Glen Echo, MD, USA. Jost B. Jonas serves as a consultant for Mundipharma Co. (Cambridge, UK), patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and is patent applicant with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15,000 771.4). Paul W. Franks has been a paid consultant in the design of a personalized Nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical Companies as part of European Union Innovative Medicines Initiative (IMI) Projects. Terho Lehtimäki is employed by Fimlab Ltd. Ozren Polasek is employed by Gen-info Ltd. The remaining authors declare no competing interests. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

AB - Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

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U2 - 10.1038/s41467-018-08008-w

DO - 10.1038/s41467-018-08008-w

M3 - Article

C2 - 30670697

AN - SCOPUS:85060388984

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 376

ER -

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Abstract

Bibliographical note

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