Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Gemma Cadby; Corey Giles; Phillip E Melton; Kevin Huynh; Natalie A Mellett; Thy Duong; Anh Nguyen; Michelle Cinel; Alex Smith; Gavriel Olshansky; Tingting Wang; Marta Brozynska; Mike Inouye; Nina S McCarthy; Amir Ariff; Joseph Hung; Jennie Hui; John Beilby; Marie-Pierre Dubé; Gerald F Watts; Sonia Shah; Naomi R Wray; Wei Ling Florence Lim; Pratishtha Chatterjee; Ian Martins; Simon M Laws; Tenielle Porter; Michael Vacher; Ashley I Bush; Christopher C Rowe; Victor L Villemagne; David Ames; Colin L Masters; Kevin Taddei; Matthias Arnold; Gabi Kastenmüller; Kwangsik Nho; Andrew J Saykin; Xianlin Han; Rima Kaddurah-Daouk; Ralph N Martins; John Blangero; Peter J Meikle; Eric K Moses

doi:10.1038/s41467-022-30875-7

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Gemma Cadby, Corey Giles, Phillip E Melton, Kevin Huynh, Natalie A Mellett, Thy Duong, Anh Nguyen, Michelle Cinel, Alex Smith, Gavriel Olshansky, Tingting Wang, Marta Brozynska, Mike Inouye, Nina S McCarthy, Amir Ariff, Joseph Hung, Jennie Hui, John Beilby, Marie-Pierre Dubé, Gerald F WattsSonia Shah, Naomi R Wray, Wei Ling Florence Lim, Pratishtha Chatterjee, Ian Martins, Simon M Laws, Tenielle Porter, Michael Vacher, Ashley I Bush, Christopher C Rowe, Victor L Villemagne, David Ames, Colin L Masters, Kevin Taddei, Matthias Arnold, Gabi Kastenmüller, Kwangsik Nho, Andrew J Saykin, Xianlin Han, Rima Kaddurah-Daouk, Ralph N Martins, John Blangero, Peter J Meikle, Eric K Moses

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

49 Citations (Scopus)

Abstract

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10 -3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

Original language	English
Article number	3124
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30875-7
Publication status	Published - Dec 2022

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10.1038/s41467-022-30875-7Licence: CC BY

1 Curtailed

The Busselton Family Heart Study
Moses, E. (Investigator 01), Meikle, P. (Investigator 02), Blangero, J. (Investigator 03), Melton, P. (Investigator 04), Hung, J. (Investigator 05), Beilby, J. (Investigator 06), Cadby, G. (Investigator 07), Dubé, M. P. (Investigator 08), Van Bockxmeer, F. (Investigator 09) & Watts, G. (Investigator 10)
NHMRC National Health and Medical Research Council
1/01/16 → 9/10/20
Project: Research

49 Citations
1 Preprint

Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease
Cadby, G., Giles, C., Melton, P. E., Huynh, K., Mellett, N. A., Duong, T., Nguyen, A., Cinel, M., Smith, A., Olshansky, G., Wang, T., Brozynska, M., Inouye, M., McCarthy, N. S., Ariff, A., Hung, J., Hui, J., Beilby, J., Dubé, M.-P. & Watts, G. F. & 24 others, Shah, S., Wray, N. R., Lim, W. L. F., Chatterjee, P., Martins, I., Laws, S. M., Porter, T., Vacher, M., Bush, A. I., Rowe, C. C., Villemagne, V. L., Ames, D., Masters, C. L., Taddei, K., Arnold, M., Kastenmüller, G., Nho, K., Saykin, A. J., Han, X., Kaddurah-Daouk, R., Martins, R. N., Blangero, J., Meikle, P. J. & Moses, E. K., 20 Aug 2021, medRxiv.
Research output: Working paper › Preprint

Cite this

Cadby, G., Giles, C., Melton, P. E., Huynh, K., Mellett, N. A., Duong, T., Nguyen, A., Cinel, M., Smith, A., Olshansky, G., Wang, T., Brozynska, M., Inouye, M., McCarthy, N. S., Ariff, A., Hung, J., Hui, J., Beilby, J., Dubé, M.-P., ... Moses, E. K. (2022). Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease. Nature Communications, 13(1), Article 3124. https://doi.org/10.1038/s41467-022-30875-7

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title = "Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease",

abstract = "We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10 -3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases. ",

keywords = "Coronary Artery Disease/genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis, Humans, Lipidomics, Lipids, Polymorphism, Single Nucleotide",

author = "Gemma Cadby and Corey Giles and Melton, {Phillip E} and Kevin Huynh and Mellett, {Natalie A} and Thy Duong and Anh Nguyen and Michelle Cinel and Alex Smith and Gavriel Olshansky and Tingting Wang and Marta Brozynska and Mike Inouye and McCarthy, {Nina S} and Amir Ariff and Joseph Hung and Jennie Hui and John Beilby and Marie-Pierre Dub{\'e} and Watts, {Gerald F} and Sonia Shah and Wray, {Naomi R} and Lim, {Wei Ling Florence} and Pratishtha Chatterjee and Ian Martins and Laws, {Simon M} and Tenielle Porter and Michael Vacher and Bush, {Ashley I} and Rowe, {Christopher C} and Villemagne, {Victor L} and David Ames and Masters, {Colin L} and Kevin Taddei and Matthias Arnold and Gabi Kastenm{\"u}ller and Kwangsik Nho and Saykin, {Andrew J} and Xianlin Han and Rima Kaddurah-Daouk and Martins, {Ralph N} and John Blangero and Meikle, {Peter J} and Moses, {Eric K}",

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Cadby, G, Giles, C, Melton, PE, Huynh, K, Mellett, NA, Duong, T, Nguyen, A, Cinel, M, Smith, A, Olshansky, G, Wang, T, Brozynska, M, Inouye, M, McCarthy, NS, Ariff, A, Hung, J , Hui, J , Beilby, J, Dubé, M-P, Watts, GF, Shah, S, Wray, NR, Lim, WLF, Chatterjee, P, Martins, I, Laws, SM, Porter, T, Vacher, M, Bush, AI, Rowe, CC, Villemagne, VL, Ames, D, Masters, CL, Taddei, K, Arnold, M, Kastenmüller, G, Nho, K, Saykin, AJ, Han, X, Kaddurah-Daouk, R, Martins, RN, Blangero, J, Meikle, PJ & Moses, EK 2022, 'Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease', Nature Communications, vol. 13, no. 1, 3124. https://doi.org/10.1038/s41467-022-30875-7

TY - JOUR

T1 - Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

AU - Cadby, Gemma

AU - Giles, Corey

AU - Melton, Phillip E

AU - Huynh, Kevin

AU - Mellett, Natalie A

AU - Duong, Thy

AU - Nguyen, Anh

AU - Cinel, Michelle

AU - Smith, Alex

AU - Olshansky, Gavriel

AU - Wang, Tingting

AU - Brozynska, Marta

AU - Inouye, Mike

AU - McCarthy, Nina S

AU - Ariff, Amir

AU - Hung, Joseph

AU - Hui, Jennie

AU - Beilby, John

AU - Dubé, Marie-Pierre

AU - Watts, Gerald F

AU - Shah, Sonia

AU - Wray, Naomi R

AU - Lim, Wei Ling Florence

AU - Chatterjee, Pratishtha

AU - Martins, Ian

AU - Laws, Simon M

AU - Porter, Tenielle

AU - Vacher, Michael

AU - Bush, Ashley I

AU - Rowe, Christopher C

AU - Villemagne, Victor L

AU - Ames, David

AU - Masters, Colin L

AU - Taddei, Kevin

AU - Arnold, Matthias

AU - Kastenmüller, Gabi

AU - Nho, Kwangsik

AU - Saykin, Andrew J

AU - Han, Xianlin

AU - Kaddurah-Daouk, Rima

AU - Martins, Ralph N

AU - Blangero, John

AU - Meikle, Peter J

AU - Moses, Eric K

PY - 2022/12

Y1 - 2022/12

N2 - We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10 -3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

AB - We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10 -3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

KW - Coronary Artery Disease/genetics

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Homeostasis

KW - Humans

KW - Lipidomics

KW - Lipids

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/s41467-022-30875-7

DO - 10.1038/s41467-022-30875-7

M3 - Article

C2 - 35668104

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3124

ER -

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Abstract

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The Busselton Family Heart Study

Research output

Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

Cite this