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

被引：59

作者：

Cadby, Gemma ^{[1
]}

Giles, Corey ^{[2
,3
,29
]}

Melton, Phillip E. ^{[1
,4
]}

Huynh, Kevin ^{[2
,3
]}

Mellett, Natalie A. ^{[2
]}

Thy Duong ^{[2
]}

Anh Nguyen ^{[2
]}

Cinel, Michelle ^{[2
]}

Smith, Alex ^{[2
]}

Olshansky, Gavriel ^{[2
,3
]}

Wang, Tingting ^{[2
,3
]}

Brozynska, Marta ^{[2
]}

Inouye, Mike ^{[2
]}

McCarthy, Nina S. ^{[5
]}

Ariff, Amir ^{[6
]}

Hung, Joseph ^{[7
,8
,9
]}

Hui, Jennie ^{[9
,10
]}

Beilby, John ^{[9
,10
]}

Dube, Marie-Pierre ^{[11
]}

Watts, Gerald F. ^{[7
,12
]}

Shah, Sonia ^{[13
]}

Wray, Naomi R. ^{[13
,14
]}

Lim, Wei Ling Florence ^{[15
,16
]}

Chatterjee, Pratishtha ^{[15
,17
,18
]}

Martins, Ian ^{[15
]}

Laws, Simon M. ^{[19
,20
,21
]}

Porter, Tenielle ^{[19
,20
,21
]}

Vacher, Michael ^{[19
,20
,22
]}

Bush, Ashley, I ^{[23
]}

Rowe, Christopher C. ^{[23
,24
]}

Villemagne, Victor L. ^{[24
,25
]}

Ames, David ^{[26
,27
]}

Masters, Colin L. ^{[23
]}

Taddei, Kevin ^{[15
]}

Arnold, Matthias ^{[28
,29
]}

Kastenmueller, Gabi ^{[29
]}

Nho, Kwangsik ^{[30
,31
,32
]}

Saykin, Andrew J. ^{[30
,32
,33
]}

Han, Xianlin ^{[34
]}

Kaddurah-Daouk, Rima ^{[28
,35
,36
]}

Martins, Ralph N. ^{[15
,16
,17
,18
]}

Blangero, John ^{[37
]}

Meikle, Peter J. ^{[2
,3
,38
]}

Moses, Eric K. ^{[4
,5
]}

机构：

[1] Univ Western Australia, Sch Populat & Global Hlth, Crawley, WA, Australia

[2] Baker Heart & Diabet Inst, Melbourne, Vic, Australia

[3] Univ Melbourne, Baker Dept Cardiometab Hlth, Melbourne, Vic, Australia

[4] Univ Tasmania, Menzies Res Inst, Hobart, Tas, Australia

[5] Univ Western Australia, Sch Biomed Sci, Crawley, WA, Australia

[6] Univ New South Wales, Sch Womens & Childrens Hlth, Sydney, NSW, Australia

[7] Univ Western Australia, Sch Med, Crawley, WA, Australia

[8] Sir Charles Gairdner Hosp, Dept Cardiovasc Med, Perth, WA, Australia

[9] Busselton Populat Med Res Inst Inc, Perth, WA, Australia

[10] PathWest Lab Med WA, Perth, WA, Australia

[11] Univ Montreal, Montreal Heart Inst, Beaulieu Saucier Pharmacogen Ctr, Montreal, PQ, Canada

[12] Royal Perth Hosp, Dept Cardiol, Lipid Disorders Clin, Perth, WA, Australia

[13] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[14] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[15] Edith Cowan Univ, Sch Med & Hlth Sci, Joondalup, WA, Australia

[16] Cooperat Res Ctr CRC Mental Hlth, Joondalup, WA, Australia

[17] Macquarie Univ, Dept Biomed Sci, N Ryde, NSW, Australia

[18] KaRa Inst Neurol Dis, Sydneymacquarie Pl, NSW, Australia

[19] Edith Cowan Univ, Ctr Precis Hlth, Joondalup, WA, Australia

[20] Edith Cowan Univ, Sch Med & Hlth Sci, Collaborat Genom Grp, Joondalup, WA, Australia

[21] Curtin Univ, Curtin Hlth Innovat Res Inst, Perth, WA, Australia

[22] CSIRO, Australian E Hlth Res Ctr, Hlth & Biosecur, Floreat, WA, Australia

[23] Univ Melbourne, Florey Dept Neurosci & Mental Hlth, Melbourne, Vic, Australia

[24] Austin Hlth, Dept Mol Imaging & Therapy, Heidelberg, Vic, Australia

[25] Univ Melbourne, Dept Med, Austin Hlth, Heidelberg, Vic, Australia

[26] Natl Ageing Res Inst, Parkville, Vic, Australia

[27] Univ Melbourne, Acad Unit Psychiat Old Age, St Georges Hosp, Kew, Vic, Australia

[28] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA

[29] Helmholtz Zentrum Munchen, Inst Computat Biol, German Res Ctr Environm Hlth, Neuherberg, Germany

[30] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA

[31] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA

[32] Indiana Univ Sch Med, Indiana Alzheimers Dis Res Ctr, Indianapolis, IN 46202 USA

[33] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[34] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA

[35] Duke Univ, Duke Inst Brain Sci, Durham, NC USA

[36] Duke Univ, Dept Med, Durham, NC USA

[37] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX USA

[38] Monash Univ, Melbourne, Vic, Australia

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

美国国家卫生研究院; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 加拿大健康研究院;

关键词：

DENSITY-LIPOPROTEIN CHOLESTEROL; LIFE-STYLE AIBL; WIDE ASSOCIATION; HEPATIC LIPASE; GENOME; PLASMA; METAANALYSIS; COMPONENTS; PREDICTION; BIOMARKERS;

D O I：

10.1038/s41467-022-30875-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 similar to 456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 x 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. Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.

引用

页数：17

共 86 条

[1] An Efficient Single Phase Method for the Extraction of Plasma Lipids [J].

Alshehry, Zahir H. ;

Barlow, Christopher K. ;

Weir, Jacquelyn M. ;

Zhou, Youping ;

McConville, Malcolm J. ;

Meikle, Peter J. .

METABOLITES, 2015, 5 (02) :389-403

[2] SNiPA: an interactive, genetic variant-centered annotation browser [J].

Arnold, Matthias ;

Raffler, Johannes ;

Pfeufer, Arne ;

Suhre, Karsten ;

Kastenmueller, Gabi .

BIOINFORMATICS, 2015, 31 (08) :1334-1336

[3] Adjusting for Heritable Covariates Can Bias Effect Estimates in Genome-Wide Association Studies [J].

Aschard, Hugues ;

Vilhjalmsson, Bjarni J. ;

Joshi, Amit D. ;

Price, Alkes L. ;

Kraft, Peter .

AMERICAN JOURNAL OF HUMAN GENETICS, 2015, 96 (02) :329-339

[4] GenABEL: an R library for genome-wide association analysis [J].

Aulchenko, Yurii S. ;

Ripke, Stephan ;

Isaacs, Aaron ;

Van Duijn, Cornelia M. .

BIOINFORMATICS, 2007, 23 (10) :1294-1296

[5] Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3 [J].

Blackburn, Nicholas B. ;

Meikle, Peter J. ;

Peralta, Juan M. ;

Kumar, Satish ;

Leandro, Ana C. ;

Bellinger, Melissa A. ;

Giles, Corey ;

Huynh, Kevin ;

Mahaney, Michael C. ;

Goring, Harald H. H. ;

VandeBerg, John L. ;

Williams-Blangero, Sarah ;

Glahn, David C. ;

Duggirala, Ravindranath ;

Blangero, John ;

Michael, Laura F. ;

Curran, Joanne E. .

CIRCULATION-GENOMIC AND PRECISION MEDICINE, 2021, 14 (03) :369-378

[6] An atlas of genetic correlations across human diseases and traits [J].

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (11) :1236-+

[7] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[8] The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 [J].

Buniello, Annalisa ;

MacArthur, Jacqueline A. L. ;

Cerezo, Maria ;

Harris, Laura W. ;

Hayhurst, James ;

Malangone, Cinzia ;

McMahon, Aoife ;

Morales, Joannella ;

Mountjoy, Edward ;

Sollis, Elliot ;

Suveges, Daniel ;

Vrousgou, Olga ;

Whetzel, Patricia L. ;

Amode, Ridwan ;

Guillen, Jose A. ;

Riat, Harpreet S. ;

Trevanion, Stephen J. ;

Hall, Peggy ;

Junkins, Heather ;

Flicek, Paul ;

Burdett, Tony ;

Hindorff, Lucia A. ;

Cunningham, Fiona ;

Parkinson, Helen .

NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D1005-D1012

[9] Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study[S] [J].

Cadby, Gemma ;

Melton, Phillip E. ;

McCarthy, Nina S. ;

Giles, Corey ;

Mellett, Natalie A. ;

Huynh, Kevin ;

Hung, Joseph ;

Beilby, John ;

Dube, Marie-Pierre ;

Watts, Gerald F. ;

Blangero, John ;

Meikle, Peter J. ;

Moses, Eric K. .

JOURNAL OF LIPID RESEARCH, 2020, 61 (04) :537-545

[10] Pleiotropy of cardiometabolic syndrome with obesity-related anthropometric traits determined using empirically derived kinships from the Busselton Health Study [J].

Cadby, Gemma ;

Melton, Phillip E. ;

McCarthy, Nina S. ;

Almeida, Marcio ;

Williams-Blangero, Sarah ;

Curran, Joanne E. ;

VandeBerg, John L. ;

Hui, Jennie ;

Beilby, John ;

Musk, A. W. ;

James, Alan L. ;

Hung, Joseph ;

Blangero, John ;

Moses, Eric K. .

HUMAN GENETICS, 2018, 137 (01) :45-53

← 1 2 3 4 5 6 7 8 9 →