Novel Loci for Metabolic Networks and Multi-Tissue Expression Studies Reveal Genes for Atherosclerosis

被引：132

作者：

Inouye, Michael ^{[1
,2
,3
]}

Ripatti, Samuli ^{[4
,5
,6
]}

Kettunen, Johannes ^{[4
,5
]}

Lyytikainen, Leo-Pekka ^{[7
,8
]}

Oksala, Niku ^{[7
,8
,9
]}

Laurila, Pirkka-Pekka ^{[4
,5
,10
,11
]}

Kangas, Antti J. ^{[12
]}

Soininen, Pasi ^{[12
,13
]}

Savolainen, Markku J. ^{[12
,14
,15
]}

Viikari, Jorma ^{[16
,17
]}

Kahonen, Mika ^{[18
,19
]}

Perola, Markus ^{[5
]}

Salomaa, Veikko

Raitakari, Olli ^{[20
,21
,22
]}

Lehtimaki, Terho ^{[7
,8
]}

Taskinen, Marja-Riitta ^{[23
]}

Jaervelin, Marjo-Riitta ^{[14
,24
,25
]}

Ala-Korpela, Mika ^{[12
,13
,15
,24
]}

Palotie, Aarno ^{[10
,11
,26
,27
]}

de Bakker, Paul I. W. ^{[26
,27
,28
,29
,30
]}

机构：

[1] Univ Melbourne, Dept Pathol, Med Syst Biol, Parkville, Vic, Australia

[2] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic, Australia

[3] Walter & Eliza Hall Inst Med Res, Div Immunol, Parkville, Vic, Australia

[4] Univ Helsinki, Inst Mol Med FIMM, Helsinki, Finland

[5] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[6] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, S Cambs, England

[7] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland

[8] Tampere Univ Hosp, Fimlab Labs, Dept Clin Chem, Tampere, Finland

[9] Tampere Univ Hosp, Dept Surg, Div Vasc Surg, Tampere, Finland

[10] Helsinki Univ Hosp, Helsinki, Finland

[11] Univ Helsinki, Dept Med Genet, Helsinki, Finland

[12] Univ Oulu, Fac Med, Inst Clin Med, Oulu, Finland

[13] Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland

[14] Univ Oulu, Bioctr Oulu, Oulu, Finland

[15] Univ Oulu, Clin Res Ctr, Dept Internal Med, Oulu, Finland

[16] Turku Univ Hosp, FIN-20520 Turku, Finland

[17] Univ Turku, Dept Med, Turku, Finland

[18] Tampere Univ Hosp, Tampere, Finland

[19] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland

[20] Turku Univ Hosp, FIN-20520 Turku, Finland

[21] Univ Turku, Dept Clin Physiol, Turku, Finland

[22] Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland

[23] Univ Helsinki, Dept Med, Helsinki, Finland

[24] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[25] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, Oulu, Finland

[26] MIT, Cambridge, MA 02139 USA

[27] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA

[28] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Genet, Boston, MA 02115 USA

[29] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[30] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands

来源：

PLOS GENETICS | 2012年 / 8卷 / 08期

基金：

芬兰科学院; 澳大利亚国家健康与医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; TRAITS; POPULATION; MICE; RISK; COHORT; MUTATIONS; DISEASES; VARIANTS; ADIPOSE;

D O I：

10.1371/journal.pgen.1002907

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Association testing of multiple correlated phenotypes offers better power than univariate analysis of single traits. We analyzed 6,600 individuals from two population-based cohorts with both genome-wide SNP data and serum metabolomic profiles. From the observed correlation structure of 130 metabolites measured by nuclear magnetic resonance, we identified 11 metabolic networks and performed a multivariate genome-wide association analysis. We identified 34 genomic loci at genome-wide significance, of which 7 are novel. In comparison to univariate tests, multivariate association analysis identified nearly twice as many significant associations in total. Multi-tissue gene expression studies identified variants in our top loci, SERPINA1 and AQP9, as eQTLs and showed that SERPINA1 and AQP9 expression in human blood was associated with metabolites from their corresponding metabolic networks. Finally, liver expression of AQP9 was associated with atherosclerotic lesion area in mice, and in human arterial tissue both SERPINA1 and AQP9 were shown to be upregulated (6.3-fold and 4.6-fold, respectively) in atherosclerotic plaques. Our study illustrates the power of multi-phenotype GWAS and highlights candidate genes for atherosclerosis.

引用

页数：12

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