Exome-wide association study of plasma lipids in >300,000 individuals

被引：417

作者：

Liu, Dajiang J. ^{[1
]}

Peloso, Gina M. ^{[2
,3
]}

Yu, Haojie ^{[4
]}

Butterworth, Adam S. ^{[6
]}

Wang, Xiao ^{[7
]}

Mahajan, Anubha ^{[8
]}

Saleheen, Danish ^{[9
,10
]}

Emdin, Connor ^{[3
,11
]}

Alam, Dewan ^{[12
]}

Alves, Alexessander Couto ^{[13
]}

Amouyel, Philippe ^{[14
]}

Di Angelantonio, Emanuele ^{[6
]}

Arveiler, Dominique ^{[15
]}

Assimes, Themistocles L. ^{[16
,17
]}

Auer, Paul L. ^{[18
]}

Baber, Usman ^{[19
]}

Ballantyne, Christie M. ^{[20
]}

Bang, Lia E. ^{[21
]}

Benn, Marianne ^{[22
,23
]}

Bis, Joshua C. ^{[24
]}

Boehnke, Michael ^{[25
]}

Boerwinkle, Eric ^{[26
,27
]}

Bork-Jensen, Jette ^{[28
]}

Bottinger, Erwin P. ^{[29
]}

Brandslund, Ivan ^{[30
,31
]}

Brown, Morris ^{[32
]}

Busonero, Fabio

Caulfield, Mark J. ^{[32
,34
,35
]}

Chambers, John C. ^{[36
,37
,38
]}

Chasman, Daniel I. ^{[39
,40
]}

Chen, Y. Eugene ^{[41
]}

Chen, Yii-Der Ida ^{[42
,43
]}

Chowdhury, Rajiv

Christensen, Cramer ^{[44
]}

Chu, Audrey Y. ^{[39
,45
]}

Connell, John M. ^{[46
]}

Cucca, Francesco ^{[47
]}

Cupples, L. Adrienne ^{[2
,45
]}

Damrauer, Scott M. ^{[48
,49
]}

Davies, Gail ^{[50
,51
]}

Deary, Ian J. ^{[50
,51
]}

Dedoussis, George ^{[52
]}

Denny, Joshua C. ^{[53
,54
]}

Dominiczak, Anna ^{[55
]}

Dube, Marie-Pierre ^{[56
,57
,58
]}

Ebeling, Tapani ^{[59
,60
]}

Eiriksdottir, Gudny ^{[61
]}

Esko, Tonu ^{[3
,62
]}

Farmaki, Aliki-Eleni ^{[52
]}

Feitosa, Mary F. ^{[63
]}

机构：

[1] Penn State Coll Med, Inst Personalized Med, Dept Publ Hlth Sci, Hershey, PA USA

[2] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[3] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[5] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England

[6] Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Res Unit NI, Donor Hlth & Genom, Cambridge, England

[7] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[8] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[9] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[10] Ctr Noncommunicable Dis, Karachi, Pakistan

[11] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[12] ICDDR B, Dhaka, Bangladesh

[13] Imperial Coll London, London, England

[14] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,Risk Factors & Mol Determinant, Lille, France

[15] Univ Strasbourg, Dept Epidemiol & Publ Hlth, EA 3430, Strasbourg, France

[16] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA

[17] Stanford Univ, Sch Med, Dept Med, Stanford, CA USA

[18] Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI USA

[19] Mt Sinai Med Ctr, Icahn Sch Med Mt Sinai, Cardiovasc Inst, New York, NY 10029 USA

[20] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[21] Copenhagen Univ Hosp, Dept Cardiol, Rigshosp, Copenhagen, Denmark

[22] Rigshosp, Dept Clin Biochem, Copenhagen, Denmark

[23] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[24] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[25] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[26] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Ctr Human Genet, Houston, TX 77030 USA

[27] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[28] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[29] Ichan Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA

[30] Lillebaelt Hosp, Dept Clin Biochem, Vejle, Denmark

[31] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark

[32] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London, England

[33] CNR, Ist Ric Genet & Biomed, Cagliari, Italy

[34] Queen Mary Univ London, William Harvey Res Inst, Barts Heart Ctr, London, England

[35] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England

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

[37] Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England

[38] Imperial Coll Healthcare NHS Trust, London, England

[39] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA

[40] Harvard Med Sch, Dept Med, Boston, MA USA

[41] Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA

[42] LABioMed Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Los Angeles, CA USA

[43] LABioMed Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Med, Los Angeles, CA USA

[44] Lillebaelt Hosp, Med Dept, Vejle, Denmark

[45] NHLBI Framingham Heart Study, Framingham, MA USA

[46] Univ Dundee, Med Res Inst, Ninewells Hosp & Med Sch, Dundee, Scotland

[47] Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy

[48] Corporal Michael Crescenz VA Med Ctr, Philadelphia, PA USA

[49] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA

[50] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

来源：

NATURE GENETICS | 2017年 / 49卷 / 12期

基金：

欧洲研究理事会; 英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金;

关键词：

APOBEC-1 COMPLEMENTATION FACTOR; CODING-SEQUENCE VARIANTS; TYROSINE KINASE JAK2; MACULAR DEGENERATION; GENETIC ARCHITECTURE; LOW-FREQUENCY; CLONAL HEMATOPOIESIS; MOLECULAR-CLONING; RARE; RISK;

D O I：

10.1038/ng.3977

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

引用

页码：1758 / +

页数：14

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Exome-wide association study of plasma lipids in &gt;300,000 individuals

Exome-wide association study of plasma lipids in >300,000 individuals