Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation.
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation.
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DOI：
10.1038/s41588-022-01168-y
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发表时间：
2022-09
期刊：
影响因子：
30.8
通讯作者：
Freedman, Matthew L.
中科院分区：
文献类型：
--
作者：
Baca, Sylvan C.;Singler, Cassandra;Zacharia, Soumya;Seo, Ji-Heui;Morova, Tunc;Hach, Faraz;Ding, Yi;Schwarz, Tommer;Huang, Chia-Chi Flora;Anderson, Jacob;Fay, Andre P.;Kalita, Cynthia;Groha, Stefan;Pomerantz, Mark M.;Wang, Victoria;Linder, Simon;Sweeney, Christopher J.;Zwart, Wilbert;Lack, Nathan A.;Pasaniuc, Bogdan;Takeda, David Y.;Gusev, Alexander;Freedman, Matthew L.
许多遗传变异通过改变背景相关的基因调控来影响疾病风险。使用目前将遗传变异与稳态基因表达水平（例如表达数量性状位点（eQTL））联系起来的方法，很难从机制上研究此类变异。为了应对这一挑战，我们开发了全顺式关联研究 (CWAS)，这是一个框架，用于识别与疾病相关的染色质的基因型和等位基因特异性影响。在前列腺癌中，CWAS 确定了调节元件和雄激素受体结合位点，解释了 98 个已知前列腺癌风险位点中 52 个的关联，并发现了 17 个其他风险位点。 CWAS 暗示了前列腺癌风险中的关键发育转录因子，但由于背景依赖的基因调控，这些因子被基于 eQTL 的方法所忽视。我们通过实验验证了关联性，并证明了 CWAS 对其他表观基因组数据集和表型的可扩展性，包括对前列腺癌治疗的反应。 CWAS 是一种强大的、生物学上可解释的范例，用于研究通过影响转录调控来影响性状的变异。
Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that also associate with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor binding sites that explained the association at 52 out of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
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