Integrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers.
Integrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers.
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DOI：
10.1038/s41467-022-34888-0
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发表时间：
2022-11-19
影响因子：
16.6
通讯作者：
Guo, Xingyi
中科院分区：
文献类型：
--
作者：
He, Jingni;Wen, Wanqing;Beeghly, Alicia;Chen, Zhishan;Cao, Chen;Shu, Xiao-Ou;Zheng, Wei;Long, Quan;Guo, Xingyi
全转录组关联研究（TWAS）已经成功发现了许多假定的疾病易感基因。然而，TWAS可能由于包含非调控变体而遭受基因表达预测的不准确性。通过整合易感转录因子占据元件的先验知识，我们开发了sTF-TWAS，并证明它在模拟和真实的数据分析中优于现有的TWAS方法。在sTF-TWAS框架下，我们建立遗传模型来预测来自基因型-组织表达项目的正常乳腺、前列腺和肺组织中的选择性剪接和基因表达，并将这些模型应用于在欧洲血统人群中进行的大型全基因组关联研究（GWAS）的数据。在Bonferroni校正P < 0.05时，我们确定了354个这些癌症的推定易感基因，包括189个以前未报道的GWAS基因座和45个GWAS未报道的基因座。这些发现为人类癌症的遗传易感性提供了额外的见解。此外，我们显示了sTF-TWAS对非癌症疾病的普遍性。全转录组关联研究可以揭示与疾病有关的基因。在这里，作者用转录组范围的关联研究方法扩展了该框架，该方法结合了转录因子占用，为关联增加了组织特异性机制支持。
Transcriptome-wide association studies (TWAS) have successfully discovered many putative disease susceptibility genes. However, TWAS may suffer from inaccuracy of gene expression predictions due to inclusion of non-regulatory variants. By integrating prior knowledge of susceptible transcription factor occupied elements, we develop sTF-TWAS and demonstrate that it outperforms existing TWAS approaches in both simulation and real data analyses. Under the sTF-TWAS framework, we build genetic models to predict alternative splicing and gene expression in normal breast, prostate and lung tissues from the Genotype-Tissue Expression project and apply these models to data from large genome-wide association studies (GWAS) conducted among European-ancestry populations. At Bonferroni-corrected P < 0.05, we identify 354 putative susceptibility genes for these cancers, including 189 previously unreported in GWAS loci and 45 in loci unreported by GWAS. These findings provide additional insight into the genetic susceptibility of human cancers. Additionally, we show the generalizability of the sTF-TWAS on non-cancer diseases. Transcriptome-wide association studies can uncover genes involved in disease. Here, the authors extend the framework with a transcriptome-wide association study approach which incorporates transcription factor occupancy, adding tissue-specific mechanistic support to associations.
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影响因子：
30.8
作者：
Dunning AM;Michailidou K;Kuchenbaecker KB;Thompson D;French JD;Beesley J;Healey CS;Kar S;Pooley KA;Lopez-Knowles E;Dicks E;Barrowdale D;Sinnott-Armstrong NA;Sallari RC;Hillman KM;Kaufmann S;Sivakumaran H;Moradi Marjaneh M;Lee JS;Hills M;Jarosz M;Drury S;Canisius S;Bolla MK;Dennis J;Wang Q;Hopper JL;Southey MC;Broeks A;Schmidt MK;Lophatananon A;Muir K;Beckmann MW;Fasching PA;Dos-Santos-Silva I;Peto J;Sawyer EJ;Tomlinson I;Burwinkel B;Marme F;Guénel P;Truong T;Bojesen SE;Flyger H;González-Neira A;Perez JI;Anton-Culver H;Eunjung L;Arndt V;Brenner H;Meindl A;Schmutzler RK;Brauch H;Hamann U;Aittomäki K;Blomqvist C;Ito H;Matsuo K;Bogdanova N;Dörk T;Lindblom A;Margolin S;Kosma VM;Mannermaa A;Tseng CC;Wu AH;Lambrechts D;Wildiers H;Chang-Claude J;Rudolph A;Peterlongo P;Radice P;Olson JE;Giles GG;Milne RL;Haiman CA;Henderson BE;Goldberg MS;Teo SH;Yip CH;Nord S;Borresen-Dale AL;Kristensen V;Long J;Zheng W;Pylkäs K;Winqvist R;Andrulis IL;Knight JA;Devilee P;Seynaeve C;Figueroa J;Sherman ME;Czene K;Darabi H;Hollestelle A;van den Ouweland AM;Humphreys K;Gao YT;Shu XO;Cox A;Cross SS;Blot W;Cai Q;Ghoussaini M;Perkins BJ;Shah M;Choi JY;Kang D;Lee SC;Hartman M;Kabisch M;Torres D;Jakubowska A;Lubinski J;Brennan P;Sangrajrang S;Ambrosone CB;Toland AE;Shen CY;Wu PE;Orr N;Swerdlow A;McGuffog L;Healey S;Lee A;Kapuscinski M;John EM;Terry MB;Daly MB;Goldgar DE;Buys SS;Janavicius R;Tihomirova L;Tung N;Dorfling CM;van Rensburg EJ;Neuhausen SL;Ejlertsen B;Hansen TV;Osorio A;Benitez J;Rando R;Weitzel JN;Bonanni B;Peissel B;Manoukian S;Papi L;Ottini L;Konstantopoulou I;Apostolou P;Garber J;Rashid MU;Frost D;EMBRACE;Izatt L;Ellis S;Godwin AK;Arnold N;Niederacher D;Rhiem K;Bogdanova-Markov N;Sagne C;Stoppa-Lyonnet D;Damiola F;GEMO Study Collaborators;Sinilnikova OM;Mazoyer S;Isaacs C;Claes KB;De Leeneer K;de la Hoya M;Caldes T;Nevanlinna H;Khan S;Mensenkamp AR;HEBON;Hooning MJ;Rookus MA;Kwong A;Olah E;Diez O;Brunet J;Pujana MA;Gronwald J;Huzarski T;Barkardottir RB;Laframboise R;Soucy P;Montagna M;Agata S;Teixeira MR;kConFab Investigators;Park SK;Lindor N;Couch FJ;Tischkowitz M;Foretova L;Vijai J;Offit K;Singer CF;Rappaport C;Phelan CM;Greene MH;Mai PL;Rennert G;Imyanitov EN;Hulick PJ;Phillips KA;Piedmonte M;Mulligan AM;Glendon G;Bojesen A;Thomassen M;Caligo MA;Yoon SY;Friedman E;Laitman Y;Borg A;von Wachenfeldt A;Ehrencrona H;Rantala J;Olopade OI;Ganz PA;Nussbaum RL;Gayther SA;Nathanson KL;Domchek SM;Arun BK;Mitchell G;Karlan BY;Lester J;Maskarinec G;Woolcott C;Scott C;Stone J;Apicella C;Tamimi R;Luben R;Khaw KT;Helland Å;Haakensen V;Dowsett M;Pharoah PD;Simard J;Hall P;García-Closas M;Vachon C;Chenevix-Trench G;Antoniou AC;Easton DF;Edwards SL
通讯作者：
Edwards SL
影响因子：
30.8
作者：
Hu, Yiming;Li, Mo;Yu, Lei
通讯作者：
Yu, Lei
DOI：
10.1158/1055-9965.epi-15-0363
发表时间：
2015-11
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Guo X;Long J;Zeng C;Michailidou K;Ghoussaini M;Bolla MK;Wang Q;Milne RL;Shu XO;Cai Q;Beesley J;Kar SP;Andrulis IL;Anton-Culver H;Arndt V;Beckmann MW;Beeghly-Fadiel A;Benitez J;Blot W;Bogdanova N;Bojesen SE;Brauch H;Brenner H;Brinton L;Broeks A;Brüning T;Burwinkel B;Cai H;Canisius S;Chang-Claude J;Choi JY;Couch FJ;Cox A;Cross SS;Czene K;Darabi H;Devilee P;Droit A;Dörk T;Fasching PA;Fletcher O;Flyger H;Fostira F;Gaborieau V;García-Closas M;Giles GG;Grip M;Guénel P;Haiman CA;Hamann U;Hartman M;Hollestelle A;Hopper JL;Hsiung CN;Ito H;Jakubowska A;Johnson N;Kabisch M;Kang D;Khan S;Knight JA;Kosma VM;Lambrechts D;Le Marchand L;Li J;Lindblom A;Lophatananon A;Lubinski J;Mannermaa A;Manoukian S;Margolin S;Marme F;Matsuo K;McLean CA;Meindl A;Muir K;Neuhausen SL;Nevanlinna H;Nord S;Olson JE;Orr N;Peterlongo P;Putti TC;Rudolph A;Sangrajrang S;Sawyer EJ;Schmidt MK;Schmutzler RK;Shen CY;Shi J;Shrubsole MJ;Southey MC;Swerdlow A;Teo SH;Thienpont B;Toland AE;Tollenaar RA;Tomlinson IP;Truong T;Tseng CC;van den Ouweland A;Wen W;Winqvist R;Wu A;Yip CH;Zamora MP;Zheng Y;Hall P;Pharoah PD;Simard J;Chenevix-Trench G;kConFab Investigators;Dunning AM;Easton DF;Zheng W
通讯作者：
Zheng W
跨务基因组全基因组关联的前列腺癌荟萃分析确定了新的敏感性基因座并告知遗传风险预测。
影响因子：
30.8
作者：
Conti DV;Darst BF;Moss LC;Saunders EJ;Sheng X;Chou A;Schumacher FR;Olama AAA;Benlloch S;Dadaev T;Brook MN;Sahimi A;Hoffmann TJ;Takahashi A;Matsuda K;Momozawa Y;Fujita M;Muir K;Lophatananon A;Wan P;Le Marchand L;Wilkens LR;Stevens VL;Gapstur SM;Carter BD;Schleutker J;Tammela TLJ;Sipeky C;Auvinen A;Giles GG;Southey MC;MacInnis RJ;Cybulski C;Wokołorczyk D;Lubiński J;Neal DE;Donovan JL;Hamdy FC;Martin RM;Nordestgaard BG;Nielsen SF;Weischer M;Bojesen SE;Røder MA;Iversen P;Batra J;Chambers S;Moya L;Horvath L;Clements JA;Tilley W;Risbridger GP;Gronberg H;Aly M;Szulkin R;Eklund M;Nordström T;Pashayan N;Dunning AM;Ghoussaini M;Travis RC;Key TJ;Riboli E;Park JY;Sellers TA;Lin HY;Albanes D;Weinstein SJ;Mucci LA;Giovannucci E;Lindstrom S;Kraft P;Hunter DJ;Penney KL;Turman C;Tangen CM;Goodman PJ;Thompson IM Jr;Hamilton RJ;Fleshner NE;Finelli A;Parent MÉ;Stanford JL;Ostrander EA;Geybels MS;Koutros S;Freeman LEB;Stampfer M;Wolk A;Håkansson N;Andriole GL;Hoover RN;Machiela MJ;Sørensen KD;Borre M;Blot WJ;Zheng W;Yeboah ED;Mensah JE;Lu YJ;Zhang HW;Feng N;Mao X;Wu Y;Zhao SC;Sun Z;Thibodeau SN;McDonnell SK;Schaid DJ;West CML;Burnet N;Barnett G;Maier C;Schnoeller T;Luedeke M;Kibel AS;Drake BF;Cussenot O;Cancel-Tassin G;Menegaux F;Truong T;Koudou YA;John EM;Grindedal EM;Maehle L;Khaw KT;Ingles SA;Stern MC;Vega A;Gómez-Caamaño A;Fachal L;Rosenstein BS;Kerns SL;Ostrer H;Teixeira MR;Paulo P;Brandão A;Watya S;Lubwama A;Bensen JT;Fontham ETH;Mohler J;Taylor JA;Kogevinas M;Llorca J;Castaño-Vinyals G;Cannon-Albright L;Teerlink CC;Huff CD;Strom SS;Multigner L;Blanchet P;Brureau L;Kaneva R;Slavov C;Mitev V;Leach RJ;Weaver B;Brenner H;Cuk K;Holleczek B;Saum KU;Klein EA;Hsing AW;Kittles RA;Murphy AB;Logothetis CJ;Kim J;Neuhausen SL;Steele L;Ding YC;Isaacs WB;Nemesure B;Hennis AJM;Carpten J;Pandha H;Michael A;De Ruyck K;De Meerleer G;Ost P;Xu J;Razack A;Lim J;Teo SH;Newcomb LF;Lin DW;Fowke JH;Neslund-Dudas C;Rybicki BA;Gamulin M;Lessel D;Kulis T;Usmani N;Singhal S;Parliament M;Claessens F;Joniau S;Van den Broeck T;Gago-Dominguez M;Castelao JE;Martinez ME;Larkin S;Townsend PA;Aukim-Hastie C;Bush WS;Aldrich MC;Crawford DC;Srivastava S;Cullen JC;Petrovics G;Casey G;Roobol MJ;Jenster G;van Schaik RHN;Hu JJ;Sanderson M;Varma R;McKean-Cowdin R;Torres M;Mancuso N;Berndt SI;Van Den Eeden SK;Easton DF;Chanock SJ;Cook MB;Wiklund F;Nakagawa H;Witte JS;Eeles RA;Kote-Jarai Z;Haiman CA
通讯作者：
Haiman CA
影响因子：
30.8
作者：
Choudhuri A;Trompouki E;Abraham BJ;Colli LM;Kock KH;Mallard W;Yang ML;Vinjamur DS;Ghamari A;Sporrij A;Hoi K;Hummel B;Boatman S;Chan V;Tseng S;Nandakumar SK;Yang S;Lichtig A;Superdock M;Grimes SN;Bowman TV;Zhou Y;Takahashi S;Joehanes R;Cantor AB;Bauer DE;Ganesh SK;Rinn J;Albert PS;Bulyk ML;Chanock SJ;Young RA;Zon LI
通讯作者：
Zon LI