Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

被引：374

作者：

Zheng, Jie ^{[1
,2
]}

Haberland, Valeriia ^{[1
,2
]}

Baird, Denis ^{[1
,2
]}

Walker, Venexia ^{[1
,2
]}

Haycock, Philip C. ^{[1
,2
]}

Hurle, Mark R. ^{[3
]}

Gutteridge, Alex ^{[4
]}

Erola, Pau ^{[1
]}

Liu, Yi ^{[1
]}

Luo, Shan ^{[1
,5
]}

Robinson, Jamie ^{[1
]}

Richardson, Tom G. ^{[1
]}

Staley, James R. ^{[1
,6
]}

Elsworth, Benjamin ^{[1
]}

Burgess, Stephen ^{[6
]}

Sun, Benjamin B. ^{[6
]}

Danesh, John ^{[6
,7
,8
,9
,10
,11
,12
]}

Runz, Heiko ^{[13
]}

Maranville, Joseph C. ^{[14
]}

Martin, Hannah M. ^{[15
]}

Yarmolinsky, James ^{[1
]}

Laurin, Charles ^{[1
]}

Holmes, Michael V. ^{[1
,16
,17
,18
]}

Liu, Jimmy Z. ^{[13
,19
]}

Estrada, Karol ^{[13
]}

Santos, Rita ^{[20
]}

McCarthy, Linda ^{[4
]}

Waterworth, Dawn ^{[3
]}

Nelson, Matthew R. ^{[3
]}

Smith, George Davey ^{[2
,21
]}

Butterworth, Adam S. ^{[2
,6
,7
,8
,9
,10
,11
]}

Hemani, Gibran ^{[1
,2
]}

Scott, Robert A. ^{[2
,4
]}

Gaunt, Tom R. ^{[1
,2
,21
]}

机构：

[1] Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England

[2] Proteome MR Writing Grp, Bristol, Avon, England

[3] GlaxoSmithKline, Human Genet, Collegeville, PA USA

[4] GlaxoSmithKline, Human Genet, Stevenage, Herts, England

[5] Univ Hong Kong, Sch Publ Hlth, Li Ka Shing Fac Med, Hong Kong, Peoples R China

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

[7] Addenbrookes Hosp, Sch Clin Med, BHF Ctr Res Excellence, Cambridge, England

[8] Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England

[9] Addenbrookes Hosp, NIHR Cambridge Biomed Res Ctr, Sch Clin Med, Cambridge, England

[10] Hlth Data Res UK Cambridge, Wellcome Genome Campus, Hinxton, England

[11] Univ Cambridge, Hinxton, England

[12] Wellcome Sanger Inst, Dept Human Genet, Hinxton, England

[13] Biogen, Translat Biol, Cambridge, MA USA

[14] Celgene Corp, Informat & Predict Sci, Cambridge, MA USA

[15] Univ Edinburgh, Sch Biol Sci, Edinburgh, Midlothian, Scotland

[16] Univ Oxford, Populat Hlth Res Unit, Med Res Council, Oxford, England

[17] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England

[18] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England

[19] Oxford Univ Hosp, Oxford Biomed Res Ctr, Natl Inst Hlth Res, Oxford, England

[20] GlaxoSmithKline, Funct Genom, Stevenage, Herts, England

[21] NIHR Bristol Biomed Res Ctr, Bristol, Avon, England

来源：

NATURE GENETICS | 2020年 / 52卷 / 10期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

ASSOCIATION; INSTRUMENTS; ACTIVATION; VARIANTS; TARGETS; GENES; GWAS;

D O I：

10.1038/s41588-020-0682-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence incis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (https://www.epigraphdb.org/pqtl/).). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

引用

页码：1122 / +

页数：15

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