Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

被引：302

作者：

Ligthart, Symen ^{[1
]}

Vaez, Ahmad ^{[2
,3
]}

Vosa, Urmo ^{[4
,5
]}

Stathopoulou, Maria G. ^{[6
]}

de Vries, Paul S. ^{[1
,7
]}

Prins, Bram P. ^{[8
]}

Van der Most, Peter J. ^{[2
]}

Tanaka, Toshiko ^{[9
]}

Naderi, Elnaz ^{[2
,10
]}

Rose, Lynda M. ^{[11
]}

Wu, Ying ^{[12
]}

Karlsson, Robert ^{[13
]}

Barbalic, Maja ^{[14
]}

Lin, Honghuang ^{[15
]}

Pool, Rene ^{[16
,17
]}

Zhu, Gu ^{[18
]}

Mace, Aurelien ^{[19
,20
,21
]}

Sidore, Carlo ^{[22
]}

Trompet, Stella ^{[23
,24
]}

Mangino, Massimo ^{[25
,26
]}

Sabater-Lleal, Maria ^{[27
,28
]}

Kemp, John P. ^{[29
,30
]}

Abbasi, Ali ^{[2
,31
,32
]}

Kacprowski, Tim ^{[33
,34
,35
]}

Verweij, Niek ^{[36
]}

Smith, Albert V. ^{[37
,38
]}

Huang, Tao ^{[39
,40
]}

Marzi, Carola ^{[41
,42
]}

Feitosa, Mary F. ^{[43
]}

Lohman, Kurt K. ^{[44
]}

Kleber, Marcus E. ^{[45
]}

Milaneschi, Yuri ^{[46
,47
]}

Mueller, Christian ^{[48
,49
,50
]}

Huq, Mahmudul ^{[2
]}

Vlachopoulou, Efthymia ^{[51
]}

Lyytikainen, Leo-Pekka ^{[52
,53
]}

Oldmeadow, Christopher ^{[54
,55
]}

Deelen, Joris ^{[56
,57
]}

Perola, Markus ^{[58
]}

Zhao, Jing Hua ^{[59
]}

Feenstra, Bjarke ^{[60
]}

Amini, Marzyeh ^{[2
]}

Lahti, Jari ^{[61
,62
,63
]}

Schraut, Katharina E. ^{[64
]}

Fornage, Myriam ^{[65
,66
]}

Suktitipat, Bhoom ^{[67
]}

Chen, Wei-Min ^{[68
]}

Li, Xiaohui ^{[69
]}

Nutile, Teresa ^{[70
]}

Malerba, Giovanni ^{[71
]}

机构：

[1] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands

[3] Isfahan Univ Med Sci, Dept Bioinformat, Esfahan 8174673461, Iran

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[5] Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[6] Univ Lorraine, INSERM, IGE PCV, F-54000 Nancy, France

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

[8] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton CB10 1SA, England

[9] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA

[10] Univ Groningen, Univ Med Ctr Groningen, Dept Radiat Oncol, NL-9713 GZ Groningen, Netherlands

[11] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA

[12] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[13] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden

[14] Univ Split, Sch Med, Split 21000, Croatia

[15] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[16] Vrije Univ, Netherlands Twin Register, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands

[17] Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, NL-1081 BT Amsterdam, Netherlands

[18] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia

[19] Univ Lausanne, Dept Computat Biol, CH-1010 Lausanne, Switzerland

[20] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[21] Univ Hosp Lausanne, Inst Social & Prevent Med, CH-1010 Lausanne, Switzerland

[22] CNR, Ist Ric Genet & Biomed, I-08045 Sardinia, Italy

[23] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands

[24] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2333 ZA Leiden, Netherlands

[25] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[26] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London SE1 9RT, England

[27] Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona 08025, Spain

[28] Karolinska Inst, Ctr Mol Med, Cardiovasc Med Unit, Dept Med, S-17176 Stockholm, Sweden

[29] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia

[30] Univ Bristol, Bristol Med Sch, MRC, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England

[31] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9713 GZ Groningen, Netherlands

[32] Univ Cambridge, Sch Med, Inst Metab Sci, MRC,Epidemiol Unit,Addenbrookes Hosp, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[33] Univ Med, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany

[34] Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany

[35] German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany

[36] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 AV Groningen, Netherlands

[37] Iceland Heart Assoc, IS-201 Kopavogur, Iceland

[38] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[39] Peking Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Beijing 100191, Peoples R China

[40] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[41] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Inst Epidemiol 2, D-85764 Neuherberg, Germany

[42] German Ctr Diabet Res, Partner Site Munich, D-85764 Munich, Germany

[43] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA

[44] Wake Forest Univ Hlth Sci, Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA

[45] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, D-68167 Mannheim, Germany

[46] Univ Amsterdam, Med Ctr, GGZ InGeest Res & Innovat, Dept Psychiat,Amsterdam Neurosci, NL-1081 HJ Amsterdam, Netherlands

[47] Univ Amsterdam, Med Ctr, GGZ InGeest Res & Innovat, Amsterdam Publ Hlth Res Inst, NL-1081 HJ Amsterdam, Netherlands

[48] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany

[49] Univ Med Ctr Schleswig Holstein, Inst Med Biometry & Stat, Campus Luebeck, D-23562 Lubeck, Germany

[50] German Ctr Cardiovasc Res, Partner Site RhineMain, D-55131 Mainz, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 103卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

C-REACTIVE PROTEIN; LD SCORE REGRESSION; MENDELIAN RANDOMIZATION; WIDE ASSOCIATION; SCHIZOPHRENIA; INSTRUMENTS; HEART; IMMUNITY; RISK;

D O I：

10.1016/j.ajhg.2018.09.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 x 10(-8)). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

引用

页码：691 / 706

页数：16

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