Significant impact of miRNA-target gene networks on genetics of human complex traits

被引：34

作者：

Okada, Yukinori ^{[1
,2
]}

Muramatsu, Tomoki ^{[3
,4
]}

Suita, Naomasa ^{[1
,5
]}

Kanai, Masahiro ^{[1
]}

Kawakami, Eiryo ^{[6
]}

Iotchkova, Valentina ^{[7
,8
]}

Soranzo, Nicole ^{[7
,8
]}

Inazawa, Johji ^{[3
,4
,9
]}

Tanaka, Toshihiro ^{[1
,9
,10
]}

机构：

[1] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Tokyo 1138510, Japan

[2] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan

[3] Tokyo Med & Dent Univ, Dept Mol Cytogenet, Med Res Inst, Tokyo 1138510, Japan

[4] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Tokyo 1138510, Japan

[5] Ono Pharmaceut CO LTD, Tsukuba Res Inst, Adv Med Res Labs, Tsukuba, Ibaraki 3004247, Japan

[6] RIKEN Ctr Integrat Med Sci, Lab Dis Syst Modeling, Yokohama, Kanagawa 2300045, Japan

[7] Wellcome Trust Sanger Inst, Human Genet, Genome Campus, Hinxton CB10 1HH, Cambs, England

[8] Univ Cambridge, Dept Haematol, Hills Rd, Cambridge CB2 0AH, England

[9] Tokyo Med & Dent Univ, Bioresource Res Ctr, Tokyo 1138510, Japan

[10] RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa 2300045, Japan

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

日本科学技术振兴机构; 日本学术振兴会; 英国惠康基金;

关键词：

LOCI; ASSOCIATIONS; ARCHITECTURE; PREDICTION; RESOURCE; DATABASE; UPDATE; RISK; SITE; AGE;

D O I：

10.1038/srep22223

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 impact of microRNA (miRNA) on the genetics of human complex traits, especially in the context of miRNA-target gene networks, has not been fully assessed. Here, we developed a novel analytical method, MIGWAS, to comprehensively evaluate enrichment of genome-wide association study (GWAS) signals in miRNA-target gene networks. We applied the method to the GWAS results of the 18 human complex traits from >1.75 million subjects, and identified significant enrichment in rheumatoid arthritis (RA), kidney function, and adult height (P < 0.05/18 = 0.0028, most significant enrichment in RA with P = 1.7 x 10(-4)). Interestingly, these results were consistent with current literature-based knowledge of the traits on miRNA obtained through the NCBI PubMed database search (adjusted P = 0.024). Our method provided a list of miRNA and target gene pairs with excess genetic association signals, part of which included drug target genes. We identified a miRNA (miR-4728-5p) that downregulates PADI2, a novel RA risk gene considered as a promising therapeutic target (rs761426, adjusted P = 2.3 x 10(-9)). Our study indicated the significant impact of miRNA-target gene networks on the genetics of human complex traits, and provided resources which should contribute to drug discovery and nucleic acid medicine.

引用

页数：9

共 46 条

[1] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[2] A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease [J].

Brest, Patrick ;

Lapaquette, Pierre ;

Souidi, Mouloud ;

Lebrigand, Kevin ;

Cesaro, Annabelle ;

Vouret-Craviari, Valerie ;

Mari, Bernard ;

Barbry, Pascal ;

Mosnier, Jean-Francois ;

Hebuterne, Xavier ;

Harel-Bellan, Annick ;

Mograbi, Baharia ;

Darfeuille-Michaud, Arlette ;

Hofman, Paul .

NATURE GENETICS, 2011, 43 (03) :242-U24

[3] PADI2 Is Significantly Associated with Rheumatoid Arthritis [J].

Chang, Xiaotian ;

Xia, Yifang ;

Pan, Jihong ;

Meng, Qingsong ;

Zhao, Yan ;

Yan, Xinfeng .

PLOS ONE, 2013, 8 (12)

[4] Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk [J].

Ehret, Georg B. ;

Munroe, Patricia B. ;

Rice, Kenneth M. ;

Bochud, Murielle ;

Johnson, Andrew D. ;

Chasman, Daniel I. ;

Smith, Albert V. ;

Tobin, Martin D. ;

Verwoert, Germaine C. ;

Hwang, Shih-Jen ;

Pihur, Vasyl ;

Vollenweider, Peter ;

O'Reilly, Paul F. ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Teumer, Alexander ;

Glazer, Nicole L. ;

Launer, Lenore ;

Zhao, Jing Hua ;

Aulchenko, Yurii ;

Heath, Simon ;

Sober, Siim ;

Parsa, Afshin ;

Luan, Jian'an ;

Arora, Pankaj ;

Dehghan, Abbas ;

Zhang, Feng ;

Lucas, Gavin ;

Hicks, Andrew A. ;

Jackson, Anne U. ;

Peden, John F. ;

Tanaka, Toshiko ;

Wild, Sarah H. ;

Rudan, Igor ;

Igl, Wilmar ;

Milaneschi, Yuri ;

Parker, Alex N. ;

Fava, Cristiano ;

Chambers, John C. ;

Fox, Ervin R. ;

Kumari, Meena ;

Go, Min Jin ;

van der Harst, Pim ;

Kao, Wen Hong Linda ;

Sjogren, Marketa ;

Vinay, D. G. ;

Alexander, Myriam ;

Tabara, Yasuharu ;

Shaw-Hawkins, Sue ;

Whincup, Peter H. .

NATURE, 2011, 478 (7367) :103-109

[5] Non-coding RNAs in human disease [J].

Esteller, Manel .

NATURE REVIEWS GENETICS, 2011, 12 (12) :861-874

[6] Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture [J].

Estrada, Karol ;

Styrkarsdottir, Unnur ;

Evangelou, Evangelos ;

Hsu, Yi-Hsiang ;

Duncan, Emma L. ;

Ntzani, Evangelia E. ;

Oei, Ling ;

Albagha, Omar M. E. ;

Amin, Najaf ;

Kemp, John P. ;

Koller, Daniel L. ;

Li, Guo ;

Liu, Ching-Ti ;

Minster, Ryan L. ;

Moayyeri, Alireza ;

Vandenput, Liesbeth ;

Willner, Dana ;

Xiao, Su-Mei ;

Yerges-Armstrong, Laura M. ;

Zheng, Hou-Feng ;

Alonso, Nerea ;

Eriksson, Joel ;

Kammerer, Candace M. ;

Kaptoge, Stephen K. ;

Leo, Paul J. ;

Thorleifsson, Gudmar ;

Wilson, Scott G. ;

Wilson, James F. ;

Aalto, Ville ;

Alen, Markku ;

Aragaki, Aaron K. ;

Aspelund, Thor ;

Center, Jacqueline R. ;

Dailiana, Zoe ;

Duggan, David J. ;

Garcia, Melissa ;

Garcia-Giralt, Natalia ;

Giroux, Sylvie ;

Hallmans, Goran ;

Hocking, Lynne J. ;

Husted, Lise Bjerre ;

Jameson, Karen A. ;

Khusainova, Rita ;

Kim, Ghi Su ;

Kooperberg, Charles ;

Koromila, Theodora ;

Kruk, Marcin ;

Laaksonen, Marika ;

Lacroix, Andrea Z. ;

Lee, Seung Hun .

NATURE GENETICS, 2012, 44 (05) :491-+

[7] Inhibiting citrullination in rheumatoid arthritis: taking fuel from the fire [J].

Fisher, Benjamin A. C. ;

Venables, Patrick J. .

ARTHRITIS RESEARCH & THERAPY, 2012, 14 (01)

[8]

Fritsche L. G, 2013, NAT GENET, V45

[9] Seven new loci associated with age-related macular degeneration [J].

Fritsche, Lars G. ;

Chen, Wei ;

Schu, Matthew ;

Yaspan, Brian L. ;

Yu, Yi ;

Thorleifsson, Gudmar ;

Zack, Donald J. ;

Arakawa, Satoshi ;

Cipriani, Valentina ;

Ripke, Stephan ;

Igo, Robert P., Jr. ;

Buitendijk, Gabrielle H. S. ;

Sim, Xueling ;

Weeks, Daniel E. ;

Guymer, Robyn H. ;

Merriam, Joanna E. ;

Francis, Peter J. ;

Hannum, Gregory ;

Agarwal, Anita ;

Armbrecht, Ana Maria ;

Audo, Isabelle ;

Aung, Tin ;

Barile, Gaetano R. ;

Benchaboune, Mustapha ;

Bird, Alan C. ;

Bishop, Paul N. ;

Branham, Kari E. ;

Brooks, Matthew ;

Brucker, Alexander J. ;

Cade, William H. ;

Cain, Melinda S. ;

Campochiaroll, Peter A. ;

Chan, Chi-Chao ;

Cheng, Ching-Yu ;

Chew, Emily Y. ;

Chin, Kimberly A. ;

Chowers, Itay ;

Clayton, David G. ;

Cojocaru, Radu ;

Conley, Yvette P. ;

Cornes, Belinda K. ;

Daly, Mark J. ;

Dhillon, Baljean ;

Edwards, Albert ;

Evangelou, Evangelos ;

Fagemess, Jesen ;

Ferreyra, Henry A. ;

Friedman, James S. ;

Geirsdottir, Asbjorg ;

George, Ronnie J. .

NATURE GENETICS, 2013, 45 (04) :433-439

[10] The regulatory effect of miRNAs is a heritable genetic trait in humans [J].

Geeleher, Paul ;

Huang, R. Stephanie ;

Gamazon, Eric R. ;

Golden, Aaron ;

Seoighe, Cathal .

BMC GENOMICS, 2012, 13

← 1 2 3 4 5 →