A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus.
A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus.
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双等位基因多核苷酸长度多态性解释了5p15.33前列腺癌风险基因座的功能因果关系。
DOI：
10.1038/s41467-023-40616-z
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发表时间：
2023-08-23
影响因子：
16.6
通讯作者：
Freedman, Matthew L.
中科院分区：
文献类型：
--
作者：
Spisak, Sandor;Tisza, Viktoria;Nuzzo, Pier Vitale;Seo, Ji-Heui;Pataki, Balint;Ribli, Dezso;Sztupinszki, Zsofia;Bell, Connor;Rohanizadegan, Mersedeh;Stillman, David R.;Alaiwi, Sarah Abou;Bartels, Alan B.;Papp, Marton;Shetty, Anamay;Abbasi, Forough;Lin, Xianzhi;Lawrenson, Kate;Gayther, Simon A.;Pomerantz, Mark;Baca, Sylvan;Solymosi, Norbert;Csabai, Istvan;Szallasi, Zoltan;Gusev, Alexander;Freedman, Matthew L.
迄今为止，单核苷酸多态性（SNP）已成为全基因组关联研究（GWAS）中研究最深入的一类多态性，然而，其他类别，如插入-缺失或多核苷酸长度多态性（MNLP）也可能带来疾病风险。多个报告显示，5p15.33前列腺癌风险区域是易洛魁同源框4（IRX 4）转录物的特别强的表达数量性状位点（eQTL）。在这里，我们使用表观基因组和基因组编辑证明了双等位基因（21和47个碱基对（bp））MNLP是调节IRX 4转录水平的因果变体。在LNCaP前列腺癌细胞（21 bp短等位基因纯合）中，47 bp长等位基因的单拷贝敲入有效地改变了染色质状态，使雄激素受体（AR）的从头功能性结合与染色质可及性增加、组蛋白3赖氨酸27乙酰化（H3 K27 ac）和IRX 4表达上调约3倍相关。我们进一步表明，MNLP是在两个额外的前列腺癌风险基因座的最强的候选易感性变异。我们估计，至少5%的前列腺癌风险位点可以用功能性非SNP因果变异来解释，这可能对其他癌症GWAS有更广泛的影响。更一般地说，我们的研究结果强调了调查其他类别的遗传变异作为人类特征的因果介质的重要性。在这里，作者在功能上描述了一种与前列腺癌相关的复杂遗传变异，该变异通过表观遗传激活调节IRX 4表达。这项工作突出了非单核苷酸多态性的因果变异在解释疾病风险的意义。
To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits. Here, the authors functionally characterize a complex genetic variant relevant in prostate cancer that regulates IRX4 expression through epigenetic activation. This work highlights the significance of non-single nucleotide polymorphism causal variants in explaining disease risk.
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影响因子：
2.7
作者：
Bruneau, BG;Bao, ZZ;Seidman, CE
通讯作者：
Seidman, CE
单细胞染色质可及性揭示了调节变化的原理。
影响因子：
64.8
作者：
Buenrostro JD;Wu B;Litzenburger UM;Ruff D;Gonzales ML;Snyder MP;Chang HY;Greenleaf WJ
通讯作者：
Greenleaf WJ
影响因子：
30.8
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.
通讯作者：
Freedman, Matthew L.
影响因子：
64.8
作者：
Ley, Timothy J.;Mardis, Elaine R.;Ding, Li;Fulton, Bob;McLellan, Michael D.;Chen, Ken;Dooling, David;Dunford-Shore, Brian H.;McGrath, Sean;Hickenbotham, Matthew;Cook, Lisa;Abbott, Rachel;Larson, David E.;Koboldt, Dan C.;Pohl, Craig;Smith, Scott;Hawkins, Amy;Abbott, Scott;Locke, Devin;Hillier, LaDeana W.;Miner, Tracie;Fulton, Lucinda;Magrini, Vincent;Wylie, Todd;Glasscock, Jarret;Conyers, Joshua;Sander, Nathan;Shi, Xiaoqi;Osborne, John R.;Minx, Patrick;Gordon, David;Chinwalla, Asif;Zhao, Yu;Ries, Rhonda E.;Payton, Jacqueline E.;Westervelt, Peter;Tomasson, Michael H.;Watson, Mark;Baty, Jack;Ivanovich, Jennifer;Heath, Sharon;Shannon, William D.;Nagarajan, Rakesh;Walter, Matthew J.;Link, Daniel C.;Graubert, Timothy A.;DiPersio, John F.;Wilson, Richard K.
通讯作者：
Wilson, Richard K.
影响因子：
16.6
作者：
Dadaev T;Saunders EJ;Newcombe PJ;Anokian E;Leongamornlert DA;Brook MN;Cieza-Borrella C;Mijuskovic M;Wakerell S;Olama AAA;Schumacher FR;Berndt SI;Benlloch S;Ahmed M;Goh C;Sheng X;Zhang Z;Muir K;Govindasami K;Lophatananon A;Stevens VL;Gapstur SM;Carter BD;Tangen CM;Goodman P;Thompson IM Jr;Batra J;Chambers S;Moya L;Clements J;Horvath L;Tilley W;Risbridger G;Gronberg H;Aly M;Nordström T;Pharoah P;Pashayan N;Schleutker J;Tammela TLJ;Sipeky C;Auvinen A;Albanes D;Weinstein S;Wolk A;Hakansson N;West C;Dunning AM;Burnet N;Mucci L;Giovannucci E;Andriole G;Cussenot O;Cancel-Tassin G;Koutros S;Freeman LEB;Sorensen KD;Orntoft TF;Borre M;Maehle L;Grindedal EM;Neal DE;Donovan JL;Hamdy FC;Martin RM;Travis RC;Key TJ;Hamilton RJ;Fleshner NE;Finelli A;Ingles SA;Stern MC;Rosenstein B;Kerns S;Ostrer H;Lu YJ;Zhang HW;Feng N;Mao X;Guo X;Wang G;Sun Z;Giles GG;Southey MC;MacInnis RJ;FitzGerald LM;Kibel AS;Drake BF;Vega A;Gómez-Caamaño A;Fachal L;Szulkin R;Eklund M;Kogevinas M;Llorca J;Castaño-Vinyals G;Penney KL;Stampfer M;Park JY;Sellers TA;Lin HY;Stanford JL;Cybulski C;Wokolorczyk D;Lubinski J;Ostrander EA;Geybels MS;Nordestgaard BG;Nielsen SF;Weisher M;Bisbjerg R;Røder MA;Iversen P;Brenner H;Cuk K;Holleczek B;Maier C;Luedeke M;Schnoeller T;Kim J;Logothetis CJ;John EM;Teixeira MR;Paulo P;Cardoso M;Neuhausen SL;Steele L;Ding YC;De Ruyck K;De Meerleer G;Ost P;Razack A;Lim J;Teo SH;Lin DW;Newcomb LF;Lessel D;Gamulin M;Kulis T;Kaneva R;Usmani N;Slavov C;Mitev V;Parliament M;Singhal S;Claessens F;Joniau S;Van den Broeck T;Larkin S;Townsend PA;Aukim-Hastie C;Gago-Dominguez M;Castelao JE;Martinez ME;Roobol MJ;Jenster G;van Schaik RHN;Menegaux F;Truong T;Koudou YA;Xu J;Khaw KT;Cannon-Albright L;Pandha H;Michael A;Kierzek A;Thibodeau SN;McDonnell SK;Schaid DJ;Lindstrom S;Turman C;Ma J;Hunter DJ;Riboli E;Siddiq A;Canzian F;Kolonel LN;Le Marchand L;Hoover RN;Machiela MJ;Kraft P;PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium;Freedman M;Wiklund F;Chanock S;Henderson BE;Easton DF;Haiman CA;Eeles RA;Conti DV;Kote-Jarai Z
通讯作者：
Kote-Jarai Z