An atlas of genetic scores to predict multi-omic traits

被引:49
作者
Xu, Yu [1 ,2 ,3 ]
Ritchie, Scott C. [1 ,2 ,3 ,4 ]
Liang, Yujian [5 ,6 ]
Timmers, Paul R. H. J. [7 ]
Pietzner, Maik [8 ,9 ,10 ]
Lannelongue, Loic [1 ,2 ,3 ,11 ,12 ]
Lambert, Samuel A. [1 ,2 ,3 ,4 ,11 ,12 ,13 ]
Tahir, Usman A. [14 ]
May-Wilson, Sebastian [7 ]
Foguet, Carles [1 ,2 ,3 ,11 ,12 ]
Johansson, Asa [15 ]
Surendran, Praveen [2 ]
Nath, Artika P. [1 ,16 ]
Persyn, Elodie [1 ,2 ,3 ]
Peters, James E. [17 ]
Oliver-Williams, Clare [2 ]
Deng, Shuliang
Prins, Bram [2 ]
Luan, Jian'an [8 ]
Bomba, Lorenzo [18 ,19 ]
Soranzo, Nicole [4 ,7 ,20 ,22 ]
Di Angelantonio, Emanuele [2 ,3 ,4 ,11 ,12 ,21 ,23 ]
Pirastu, Nicola [21 ,22 ]
Tai, E. Shyong [5 ,6 ,24 ,25 ]
van Dam, Rob M. [5 ,6 ,26 ,27 ]
Parkinson, Helen [13 ]
Davenport, Emma E. [18 ]
Paul, Dirk S. [2 ]
Yau, Christopher [28 ,29 ,30 ]
Gerszten, Robert E. [14 ,31 ]
Malarstig, Anders [32 ,33 ]
Danesh, John [2 ,3 ,4 ,11 ,12 ,18 ,21 ]
Sim, Xueling [5 ,6 ]
Langenberg, Claudia [8 ,9 ,10 ]
Wilson, James F. [7 ,34 ]
Butterworth, Adam S. [2 ,3 ,4 ,11 ,12 ,21 ]
Inouye, Michael [1 ,2 ,3 ,4 ,11 ,12 ,16 ,35 ]
机构
[1] Univ Cambridge, Cambridge Baker Syst Genom Initiat, Dept Publ Hlth & Primary Care, Cambridge, England
[2] Univ Cambridge, British Heart Fdn, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England
[3] Univ Cambridge, Victor Phillip Dahdaleh Heart & Lung Res Inst, Cambridge, England
[4] Univ Cambridge, Sch Clin Med, British Heart Fdn, Ctr Res Excellence, Cambridge, England
[5] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore
[6] Natl Univ Hlth Syst, Singapore, Singapore
[7] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst, Edinburgh, Midlothian, Scotland
[8] Univ Cambridge, MRC Epidemiol Unit, Inst Metab Sci, Sch Clin Med, Cambridge, England
[9] Charite Univ Med Berlin, Berlin Inst Hlth BIH, Computat Med, Berlin, Germany
[10] Queen Mary Univ London, Precis Healthcare Univ Res Inst, London, England
[11] Hlth Data Res UK Cambridge, Wellcome Genome Campus, Cambridge, England
[12] Univ Cambridge, Cambridge, England
[13] Wellcome Genome Campus, European Bioinformat Inst, European Mol Biol Lab, Hinxton, England
[14] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02215 USA
[15] Uppsala Univ, Genet & Pathol Sci Life Lab, Dept Immunol, Uppsala, Sweden
[16] Baker Heart & Diabet Inst, Cambridge Baker Syst Genom Initiat, Melbourne, Vic, Australia
[17] Imperial Coll London, Dept Immunol & Inflammat, Fac Med, London, England
[18] Wellcome Genome Campus, Wellcome Sanger Inst, Hinxton, England
[19] BioMarin Pharmaceut, Novato, CA USA
[20] Univ Cambridge, Dept Haematol, Cambridge, England
[21] Univ Cambridge, NIHR Blood & Transplant Res Unit Donor Hlth & Beh, Dept Publ Hlth & Primary Care, Cambridge, England
[22] Human Technopole, Genom Res Ctr, Milan, Italy
[23] Human Technopole, Hlth Data Sci Res Ctr, Milan, Italy
[24] Natl Univ Singapore, Dept Med, Singapore, Singapore
[25] Natl Univ Hlth Syst, Singapore, Singapore
[26] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutr Sci, Washington, DC USA
[27] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Epidemiol, Washington, DC USA
[28] Univ Oxford, Nuffield Dept Womens & Reprod Hlth, Oxford, England
[29] Univ Manchester, Fac Biol Med & Hlth, Div Informat Imaging & Data Sci, Manchester, Lancs, England
[30] Hlth Data Res UK, London, England
[31] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA USA
[32] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden
[33] Pfizer, Worldwide Res Dev & Med, Stockholm, Sweden
[34] Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland
[35] Alan Turing Inst, London, England
基金
英国科研创新办公室; 欧盟地平线“2020”;
关键词
RISK; DISEASE; BLOOD; PATHWAY; VARIANTS; TARGET; WIDE;
D O I
10.1038/s41586-023-05844-9
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
The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics(1). Here we examine a large cohort (the INTERVAL study(2); n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank(3) to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal (https://www.omicspred.org/) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
引用
收藏
页码:123 / +
页数:27
相关论文
共 85 条
[1]   Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps [J].
Adeyemo, Adebowale ;
Balaconis, Mary K. ;
Darnes, Deanna R. ;
Fatumo, Segun ;
Granados Moreno, Palmira ;
Hodonsky, Chani J. ;
Inouye, Michael ;
Kanai, Masahiro ;
Kato, Kazuto ;
Knoppers, Bartha M. ;
Lewis, Anna C. F. ;
Martin, Alicia R. ;
McCarthy, Mark I. ;
Meyer, Michelle N. ;
Okada, Yukinori ;
Richards, J. Brent ;
Richter, Lucas ;
Ripatti, Samuli ;
Rotimi, Charles N. ;
Sanderson, Saskia C. ;
Sturm, Amy C. ;
Verdugo, Ricardo A. ;
Widen, Elisabeth ;
Willer, Cristen J. ;
Wojcik, Genevieve L. ;
Zhou, Alicia .
NATURE MEDICINE, 2021, 27 (11) :1876-1884
[2]   Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development [J].
Agrawal, Sudesh ;
Febbraio, Maria ;
Podrez, Eugene ;
Cathcart, Martha K. ;
Stark, George R. ;
Chisolm, Guy M. .
CIRCULATION, 2007, 115 (23) :2939-2947
[3]   A global reference for human genetic variation [J].
Altshuler, David M. ;
Durbin, Richard M. ;
Abecasis, Goncalo R. ;
Bentley, David R. ;
Chakravarti, Aravinda ;
Clark, Andrew G. ;
Donnelly, Peter ;
Eichler, Evan E. ;
Flicek, Paul ;
Gabriel, Stacey B. ;
Gibbs, Richard A. ;
Green, Eric D. ;
Hurles, Matthew E. ;
Knoppers, Bartha M. ;
Korbel, Jan O. ;
Lander, Eric S. ;
Lee, Charles ;
Lehrach, Hans ;
Mardis, Elaine R. ;
Marth, Gabor T. ;
McVean, Gil A. ;
Nickerson, Deborah A. ;
Wang, Jun ;
Wilson, Richard K. ;
Boerwinkle, Eric ;
Doddapaneni, Harsha ;
Han, Yi ;
Korchina, Viktoriya ;
Kovar, Christie ;
Lee, Sandra ;
Muzny, Donna ;
Reid, Jeffrey G. ;
Zhu, Yiming ;
Chang, Yuqi ;
Feng, Qiang ;
Fang, Xiaodong ;
Guo, Xiaosen ;
Jian, Min ;
Jiang, Hui ;
Jin, Xin ;
Lan, Tianming ;
Li, Guoqing ;
Li, Jingxiang ;
Li, Yingrui ;
Liu, Shengmao ;
Liu, Xiao ;
Lu, Yao ;
Ma, Xuedi ;
Tang, Meifang ;
Wang, Bo .
NATURE, 2015, 526 (7571) :68-+
[4]   The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease [J].
Astle, William J. ;
Elding, Heather ;
Jiang, Tao ;
Allen, Dave ;
Ruklisa, Dace ;
Mann, Alice L. ;
Mead, Daniel ;
Bouman, Heleen ;
Riveros-Mckay, Fernando ;
Kostadima, Myrto A. ;
Lambourne, John J. ;
Sivapalaratnam, Suthesh ;
Downes, Kate ;
Kundu, Kousik ;
Bomba, Lorenzo ;
Berentsen, Kim ;
Bradley, John R. ;
Daugherty, Louise C. ;
Delaneau, Olivier ;
Freson, Kathleen ;
Garner, Stephen F. ;
Grassi, Luigi ;
Guerrero, Jose ;
Haimel, Matthias ;
Janssen-Megens, Eva M. ;
Kaan, Anita ;
Kamat, Mihir ;
Kim, Bowon ;
Mandoli, Amit ;
Marchini, Jonathan ;
Martens, Joost H. A. ;
Meacham, Stuart ;
Megy, Karyn ;
O'Connell, Jared ;
Petersen, Romina ;
Sharifi, Nilofar ;
Sheard, Simon M. ;
Staley, James R. ;
Tuna, Salih ;
van der Ent, Martijn ;
Walter, Klaudia ;
Wang, Shuang-Yin ;
Wheeler, Eleanor ;
Wilder, Steven P. ;
Iotchkova, Valentina ;
Moore, Carmel ;
Sambrook, Jennifer ;
Stunnenberg, Hendrik G. ;
Di Angelantonio, Emanuele ;
Kaptoge, Stephen .
CELL, 2016, 167 (05) :1415-+
[5]   Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl Receptor-Null Mice [J].
Babaev, Vladimir R. ;
Ding, Lei ;
Zhang, Youmin ;
May, James M. ;
Ramsey, Stephen A. ;
Vickers, Kasey C. ;
Linton, MacRae F. .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2019, 39 (02) :156-169
[6]   The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms [J].
Baldini, Chiara ;
Moriconi, Francesca Romana ;
Galimberti, Sara ;
Libby, Peter ;
De Caterina, Raffaele .
EUROPEAN HEART JOURNAL, 2021, 42 (42) :4389-+
[7]   Exploring celiac disease candidate pathways by global gene expression profiling and gene network cluster analysis [J].
Banaganapalli, Babajan ;
Mansour, Haifa ;
Mohammed, Arif ;
Alharthi, Arwa Mastoor ;
Aljuaid, Nada Mohammed ;
Nasser, Khalidah Khalid ;
Ahmad, Aftab ;
Saadah, Omar I. ;
Al-Aama, Jumana Yousuf ;
Elango, Ramu ;
Shaik, Noor Ahmad .
SCIENTIFIC REPORTS, 2020, 10 (01)
[8]   Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics [J].
Barbeira, Alvaro N. ;
Dickinson, Scott P. ;
Bonazzola, Rodrigo ;
Zheng, Jiamao ;
Wheeler, Heather E. ;
Torres, Jason M. ;
Torstenson, Eric S. ;
Shah, Kaanan P. ;
Garcia, Tzintzuni ;
Edwards, Todd L. ;
Stahl, Eli A. ;
Huckins, Laura M. ;
Nicolae, Dan L. ;
Cox, Nancy J. ;
Im, Hae Kyung .
NATURE COMMUNICATIONS, 2018, 9
[9]   Approximately independent linkage disequilibrium blocks in human populations [J].
Berisa, Tomaz ;
Pickrell, Joseph K. .
BIOINFORMATICS, 2016, 32 (02) :283-285
[10]  
Bishop C. M., 2007, Pattern Recognition and Machine Learning Information Science and Statistics, V1st